Inhibitors of serine proteases, particularly HCV NS3-NS4A protease

ABSTRACT

The present invention relates to peptidomimetic compounds that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The invention further relates to compositions comprising these compounds either for ex vivo use or for administration to a patient suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a patient by administering a composition comprising a compound of this invention.

[0001] This application claims priority to U.S. Provisional PatentApplication No. 60/343,862 filed Oct. 24, 2001.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to peptidomimetic compounds thatinhibit serine protease activity, particularly the activity of hepatitisC virus NS3-NS4A protease. As such, they act by interfering with thelife cycle of the hepatitis C virus and are also useful as antiviralagents. The invention further relates to compositions comprising thesecompounds either for ex vivo use or for administration to a patientsuffering from HCV infection. The invention also relates to methods oftreating an HCV infection in a patient by administering a compositioncomprising a compound of this invention.

BACKGROUND OF THE INVENTION

[0003] Infection by hepatitis C virus (“HCV”) is a compelling humanmedical problem. HCV is recognized as the causative agent for most casesof non-A, non-B hepatitis, with an estimated human sero-prevalence of 3%globally [A. Alberti et al., “Natural History of Hepatitis C,” J.Hepatology, 31., (Suppl. 1), pp. 17-24 (1999)]. Nearly four millionindividuals may be infected in the United States alone [M. J. Alter etal., “The Epidemiology of Viral Hepatitis in the United States,Gastroenterol. Clin. North Am., 23, pp. 437-455 (1994); M. J. Alter“Hepatitis C Virus Infection in the United States,” J. Hepatology, 31.,(Suppl. 1), pp. 88-91 (1999)].

[0004] Upon first exposure to HCV only about 20% of infected individualsdevelop acute clinical hepatitis while others appear to resolve theinfection spontaneously. In almost 70% of instances, however, the virusestablishes a chronic infection that persists for decades [S. Iwarson,“The Natural Course of Chronic Hepatitis,” FEMS Microbiology Reviews,14, pp. 201-204 (1994); D. Lavanchy, “Global Surveillance and Control ofHepatitis C,” J. Viral Hepatitis, 6, pp. 35-47 (1999)]. This usuallyresults in recurrent and progressively worsening liver inflammation,which often leads to more severe disease states such as cirrhosis andhepatocellular carcinoma [M. C. Kew, “Hepatitis C and HepatocellularCarcinoma”, FEMS Microbiology Reviews, 14, pp. 211-220 (1994); I. Saitoet. al., “Hepatitis C Virus Infection is Associated with the Developmentof Hepatocellular Carcinoma,” Proc. Natl. Acad. Sci. USA, 87, pp.6547-6549 (1990)]. Unfortunately, there are no broadly effectivetreatments for the debilitating progression of chronic HCV.

[0005] The HCV genome encodes a polyprotein of 3010-3033 amino acids [Q.L. Choo, et al., “Genetic Organization and Diversity of the Hepatitis CVirus.” Proc. Natl. Acad. Sci. USA, 88, pp. 2451-2455 (1991); N. Kato etal., “Molecular Cloning of the Human Hepatitis C Virus Genome FromJapanese Patients with Non-A, Non-B Hepatitis,” Proc. Natl. Acad. Sci.USA, 87, pp. 9524-9528 (1990); A. Takamizawa et. al., “Structure andOrganization of the Hepatitis C Virus Genome Isolated From HumanCarriers,” J. Virol., 65, pp. 1105-1113 (1991)]. The HCV nonstructural(NS) proteins are presumed to provide the essential catalytic machineryfor viral replication. The NS proteins are derived by proteolyticcleavage of the polyprotein [R. Bartenschlager et. al., “NonstructuralProtein 3 of the Hepatitis C Virus Encodes a Serine-Type ProteinaseRequired for Cleavage at the NS3/4 and NS4/5 Junctions,” J. Virol., 67,pp. 3835-3844 (1993); A. Grakoui et al., “Characterization of theHepatitis C Virus-Encoded Serine Proteinase: Determination ofProteinase-Dependent Polyprotein Cleavage Sites,” J. Virol., 67, pp.2832-2843 (1993); A. Grakoui et al., “Expression and Identification ofHepatitis C Virus Polyprotein Cleavage Products,” J. Virol., 67, pp.1385-1395 (1993); L. Tomei et al., “NS3 is a serine protease requiredfor processing of hepatitis C virus polyprotein”, J. Virol., 67, pp.4017-4026 (1993)].

[0006] The HCV NS protein 3 (NS3) contains a serine protease activitythat helps process the majority of the viral enzymes, and is thusconsidered essential for viral replication and infectivity. It is knownthat mutations in the yellow fever virus NS3 protease decreases viralinfectivity [Chambers, T. J. et. al., “Evidence that the N-terminalDomain of Nonstructural Protein NS3 From Yellow Fever Virus is a SerineProtease Responsible for Site-Specific Cleavages in the ViralPolyprotein”, Proc. Natl. Acad. Sci. USA, 87, pp. 8898-8902 (1990)]. Thefirst 181 amino acids of NS3 (residues 1027-1207 of the viralpolyprotein) have been shown to contain the serine protease domain ofNS3 that processes all four downstream sites of the HCV polyprotein [C.Lin et al., “Hepatitis C Virus NS3 Serine Proteinase: Trans-CleavageRequirements and Processing Kinetics”, J. Virol., 68, pp. 8147-8157(1994)].

[0007] The HCV NS3 serine protease and its associated cofactor, NS4A,helps process all of the viral enzymes, and is thus considered essentialfor viral replication. This processing appears to be analogous to thatcarried out by the human immunodeficiency virus aspartyl protease, whichis also involved in viral enzyme processing HIV protease inhibitors,which inhibit viral protein processing are potent antiviral agents inman, indicating that interrupting this stage of the viral life cycleresults in therapeutically active agents. Consequently it is anattractive target for drug discovery.

[0008] Several potential HCV protease inhibitors have been described inthe prior art [PCT publication Nos. WO 00/09558, WO 00/09543, WO99/64442, WO 99/07733, WO 99/07734, WO 99/50230, WO 98/46630, WO98/17679 and WO 97/43310, U.S. Pat. No. 5,990,276, M. Llinas-Brunet etal., Bioorg. Med. Chem. Lett., 8, pp. 1713-18 (1998); W. Han et al.,Bioorg. Med. Chem. Lett., 10, 711-13 (2000); R. Dunsdon et al., Bioorg.Med. Chem. Lett., 10, pp. 1571-79 (2000); M. Llinas-Brunet et al.,Bioorg. Med. Chem. Lett., 10, pp. 2267-70 (2000); and S. LaPlante etal., Bioorg. Med. Chem. Lett., 10, pp. 2271-74 (2000)]. Unfortunately,there are no serine protease inhibitors available currently as anti-HCVagents.

[0009] Furthermore, the current understanding of HCV has not led to anyother satisfactory anti-HCV agents or treatments. The only establishedtherapy for HCV disease is interferon treatment. However, interferonshave significant side effects [M. A. Wlaker et al., “Hepatitis C Virus:An Overview of Current Approaches and Progress,” DDT, 4, pp. 518-29(1999); D. Moradpour et al., “Current and Evolving Therapies forHepatitis C,” Eur. J. Gastroenterol. Hepatol., 11, pp. 1199-1202 (1999);H. L. A. Janssen et al. “Suicide Associated with Alfa-Interferon Therapyfor Chronic Viral Hepatitis,” J. Hepatol., 21, pp. 241-243 (1994); P. F.Renault et al., “Side Effects of Alpha Interferon,” Seminars in LiverDisease, 9, pp. 273-277. (1989)] and induce long term remission in onlya fraction (˜25%) of cases [O. Weiland, “Interferon Therapy in ChronicHepatitis C Virus Infection”, FEMS Microbiol. Rev., 14, pp. 279-288(1994)]. Moreover, the prospects for effective anti-HCV vaccines remainuncertain.

[0010] Thus, there is a need for more effective anti-HCV therapies. Suchinhibitors would have therapeutic potential as protease inhibitors,particularly as serine protease inhibitors, and more particularly as HCVNS3 protease inhibitors. Specifically, such compounds may be useful asantiviral agents, particularly as anti-HCV agents.

SUMMARY OF THE INVENTION

[0011] The present invention provides a compound of formula (I):

[0012] wherein:

[0013] ring A is a carbocyclic or heterocyclic ring, wherein ring A isoptionally fused to a carbocyclic, heterocyclic or heteroaryl ring;

[0014] wherein ring A has up to 3 substituents selected independentlyfrom J;

[0015] ring B is a carbocyclic or heterocyclic ring, wherein ring B isoptionally fused to a carbocyclic, heterocyclic or heteroaryl ring;

[0016] wherein ring B has up to 3 substituents selected independentlyfrom J;

[0017] J is halogen, —OR′, —NO₂, —CF₃, —OCF₃, —R′, oxo, —O-benzyl,—O-phenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′,—SO₂R′, —C(O)R′, —COOR′ or —CON(R′)₂, —OC(O)R′ wherein R′ isindependently selected from:

[0018] hydrogen,

[0019] (C1-C12)-aliphatic,

[0020] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0021] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0022] (C6-C10)-aryl,

[0023] (C6-C10)-aryl-(C1-C12)aliphatic,

[0024] (C3-C10)-heterocyclyl,

[0025] (C6-C10)-heterocyclyl-(C1-C12)aliphatic,

[0026] (C5-C10)-heteroaryl, or

[0027] (C5-C10)-heteroaryl-(C1-C12)-aliphatic;

[0028] R₁ and R₃ are independently:

[0029] (C1-C12)-aliphatic,

[0030] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0031] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0032] (C6-C10)-aryl,

[0033] (C6-C10)-aryl-(C1-C12)aliphatic,

[0034] (C3-C10)-heterocyclyl,

[0035] (C6-C10)-heterocyclyl-(C1-C12)aliphatic,

[0036] (C5-C10)-heteroaryl, or

[0037] (C5-C10)-heteroaryl-(C1-C12)-aliphatic,

[0038] wherein each of R₁ and R₃ is independently and optionallysubstituted with up to 3 substituents independently selected from J;

[0039] wherein up to 3 aliphatic carbon atoms in R₁ and R₃ may bereplaced by a heteroatom selected from O, NH, S, SO, or SO₂ in achemically stable arrangement;

[0040] R₂ and R₄ are independently

[0041] hydrogen,

[0042] (C1-C12)-aliphatic,

[0043] (C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or

[0044] (C6-C10)aryl-(C1-C12)-aliphatic,

[0045] wherein each of R₂ and R₄ is independently and optionallysubstituted with up to 3 substituents independently selected from J;

[0046] wherein up to two aliphatic carbon atoms in R₂ and R₄ may bereplaced by a heteroatom selected from O, NH, S, SO, or SO₂ in achemically stable arrangement;

[0047] Z is a carbon atom, —CHR—N—, —HN—CR— or —CHR—CHR—, —O—CHR—,—S—CHR—, —SO—CHR—, —SO₂—CHR—, or —N—;

[0048] wherein R is aliphatic, aryl, aralkyl or cycloalkyl;

[0049] R₅ is —(C1-C12) aliphatic, wherein any hydrogen is optionallysubstituted with halogen, and wherein any hydrogen or halogen atom boundto any terminal carbon atom of R₅ is optionally substituted withsulfhydryl or hydroxy;

[0050] W is selected from: —C(O)OH;

[0051] wherein each R₆ is independently:

[0052] hydrogen,

[0053] (C1-C12)-aliphatic,

[0054] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0055] (C6-C10)-aryl,

[0056] (C6-C10)-aryl-(C1-C12)aliphatic,

[0057] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0058] (C3-C10)-heterocyclyl,

[0059] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0060] (C5-C10)heteroaryl, or

[0061] (C5-C10)heteroaryl-(C1-C12)-aliphatic, or

[0062] two R₆ groups, which are bound to the same nitrogen atom, formtogether with that nitrogen atom, a (C3-C10)-heterocyclic ring;

[0063] wherein R₆ is optionally substituted with up to 3 J substituents;

[0064] each R₇ is hydroxy, alkoxy, or aryloxy; or

[0065] each R₇ is an oxygen atom linked to an aliphatic group and,together with the boron to which they are each bound, the two R₇ groupsform a 3-6 membered ring;

[0066] V is a bond, —CH(R₈)—, —N(R₈)—, —O—, —O—CH(R₈)—, —CH(R₈)—O—, —S—,—S—CH(R₈)—, —CH(R₈)—S—, —C(O)—, —C(O)—O—, —O—C(O)—, —C(O)—S—, —S—C(O)—,—C(O)—CHR₈—, —CHR₈—C(O)— —N(R₈)C(O)—, —C(O)N(R₈)—, —S(O)—, —S(O)—CH(R₈),—CH(R₈)—S(O)—, —S(O)N(R₈)—, —N(R₈)S(O)—, —S(O)—N(R₈)—CH(R₈)—,—CH(R₈)—N(R)₈—S(O)—, —N(R₈)—S(O)—CH(R₈)—, —CH(R₈)—S(O)—N(R₈)—,—CH(R₈)—S(O)₂—, —S(O)₂—CH(R₈)—, —S(O)₂N(R₈)—, —N(R₈)—S(O)₂—,—S(O)₂—N(R₈)—CHR₈—, —CHR₈—N(R₈)—S(O)₂—, —N(R₈)—S(O)₂—CHR₈ or—CH(R₈)—S(O)₂—N(R₈)—;

[0067] wherein R₈ is hydrogen or (C1-C12)-aliphatic;

[0068] T is selected from:

[0069] (C6-C10)-aryl,

[0070] (C6-C10)-aryl-(C1-C12)aliphatic,

[0071] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0072] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0073] (C3-C10)-heterocyclyl,

[0074] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0075] (C5-C10)heteroaryl, or

[0076] (C5-C10)heteroaryl-(C1-C12)-aliphatic; or

[0077] T is selected from:

[0078] wherein:

[0079] R₁₀ is:

[0080] hydrogen,

[0081] (C1-C12)-aliphatic,

[0082] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0083] (C6-C10)-aryl,

[0084] (C6-C10)-aryl-(C1-C12)aliphatic,

[0085] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0086] (C3-C10)-heterocyclyl,

[0087] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0088] (C5-C10)-heteroaryl, or

[0089] (C5-C10)-heteroaryl-(C1-C12)-aliphatic,

[0090] wherein each T is optionally substituted with up to 3 Jsubstituents;

[0091] K is a bond, (C1-C12)-aliphatic, —O—, —S—, —NR₉—, —C(O)—, or—C(O)—NR₉—, wherein R₉ is hydrogen or (C1-C12)-aliphatic; and

[0092] n is 1-3.

[0093] The present invention also provides a compound of formula (II):

[0094] wherein:

[0095] T, V, R, R₁, R₂, R₃, R₄, R₅, Z and W are as defined above forcompounds of formula (I);

[0096] ring A is a carbocyclic, heteroaryl or heterocyclic ring, whereinring A is optionally fused to an carbocyclic, heterocyclic or heteroarylring;

[0097] wherein ring A has up to 4 substituents selected independentlyfrom J;

[0098] ring C is a cycloalkyl or heterocyclic ring; and

[0099] wherein ring C has up to 3 substituents selected independentlyfrom J; wherein J is as defined above for compounds of formula (I).

[0100] The present invention also provides a compound of formula (III):

[0101] wherein:

[0102] T, V, R, R₁, R₂, R₃, R₄, R₅, Z and W are as defined above forcompounds of formula (I);

[0103] ring B is a carbocyclic or heterocyclic ring, wherein ring B isoptionally fused to a carbocyclic, heterocyclic or heteroaryl ring;

[0104] wherein ring B has up to 3 substituents selected independentlyfrom J;

[0105] ring C is a cycloalkyl or heterocyclic ring; and

[0106] wherein ring C has up to 3 substituents selected independentlyfrom J; wherein J is as defined above for compounds of formula (I).

[0107] The present invention also provides a compound of formula (IV):

[0108] wherein:

[0109] T, V, R, R₁, R₂, R₃, R₄, R₅, Z and W are as defined above forcompounds of formula (I);

[0110] ring B is a bridged bicyclic ring system containing 6-12 carbonatoms, wherein ring B is saturated or partially unsaturated; or

[0111] the ring system comprising ring B, together with the ringcontaining Z and the nitrogen atom, contains more than ten ring atoms;and

[0112] wherein ring B has up to 3 substituents selected independentlyfrom J; wherein J is as defined above for compounds of formula (I).

[0113] The invention also relates to compositions that comprise theabove compounds and the use thereof. Such compositions may be useful topre-treat invasive devices to be inserted into a patient, to treatbiological samples, such as blood, prior to administration to a patient,and for direct administration to a patient. In each case the compositionwill be used to inhibit HCV replication and to lessen the risk of or theseverity of HCV infection.

DETAILED DESCRIPTION OF THE INVENTION

[0114] In the description, the following abbreviations are used:Designation Reagent or Fragment Abu aminobutyric acid Ac acetyl AcOHacetic acid Bn benzyl Boc tert-butyloxycarbonyl Bz benzoyl Cbzcarbobenzyloxy CDI carbonyldiimidazole DCE 1,2-dichloroethane DCMdichloromethane DIEA diisopropylethylamine DMA dimethylacetamide DMAPdimethylaminopyridine DMF dimethylformamide DPPA diphenylphosphorylazideDMSO dimethylsulfoxide Et ethyl EtOAc ethyl acetate FMOC9-fluorenylmethoxycarbonyl HbtU O-benzotriazolyl-N,N,N′,N′-tetramethyluronium hexafluorophosphate HOBt N-hydroxybenzotriazole HPLChigh performance liquid chromatography Me methyl MS mass spectrometryNMP N-methyl pyrrolidinone ND not determined Pip piperidine Przpiperazine PyBrop bromo-tris-pyrrolidinophosphonium hexafluorophosphatePyr pyridine THF tetrahydrofuran TFA trifluoroacetic acid TFEtrifluoroethanol Tol toluene

[0115] The present invention provides a compound of formula (I):

[0116] wherein:

[0117] ring A is a carbocyclic or heterocyclic ring, wherein ring A isoptionally fused to a carbocyclic, heterocyclic or heteroaryl ring;

[0118] wherein ring A has up to 3 substituents selected independentlyfrom J;

[0119] ring B is a carbocyclic or heterocyclic ring, wherein ring B isoptionally fused to a carbocyclic, heterocyclic or heteroaryl ring;

[0120] wherein ring B has up to 3 substituents selected independentlyfrom J;

[0121] J is halogen, —OR′, —NO₂, —CF₃, —OCF₃, —R′, oxo, —OR′, —O-benzyl,—O-phenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′,—SO₂R′, —C(O)R′, —COOR′ or —CON(R′)₂, wherein R′ is independentlyselected from:

[0122] hydrogen,

[0123] (C1-C12)-aliphatic,

[0124] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0125] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0126] (C6-C10)-aryl,

[0127] (C6-C10)-aryl-(C1-C12)aliphatic,

[0128] (C3-C10)-heterocyclyl,

[0129] (C6-C10)-heterocyclyl-(C1-C12)aliphatic,

[0130] (C5-C10)-heteroaryl, or

[0131] (C5-C10)-heteroaryl-(C1-C12)-aliphatic;

[0132] R₁ and R₃ are independently:

[0133] (C1-C12)-aliphatic,

[0134] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0135] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0136] (C6-C10)-aryl,

[0137] (C6-C10)-aryl-(C1-C12)aliphatic,

[0138] (C3-C10)-heterocyclyl,

[0139] (C6-C10)-heterocyclyl-(C1-C12)aliphatic,

[0140] (C5-C10)-heteroaryl, or

[0141] (C5-C10)-heteroaryl-(C1-C12)-aliphatic,

[0142] wherein each of R₁ and R₃ is independently and optionallysubstituted with up to 3 substituents independently selected from J;

[0143] wherein up to 3 aliphatic carbon atoms in R₁ and R₃ may bereplaced by a heteroatom selected from O, NH, S, SO, or SO₂ in achemically stable arrangement;

[0144] R₂ and R₄ are independently

[0145] hydrogen,

[0146] (C1-C12)-aliphatic,

[0147] (C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or

[0148] (C6-C10)aryl-(C1-C12)-aliphatic,

[0149] wherein each of R₂ and R₄ is independently and optionallysubstituted with up to 3 substituents independently selected from J;

[0150] wherein up to two aliphatic carbon atoms in R₂ and R₄ may bereplaced by a heteroatom selected from O, NH, S, SO, or SO₂ in achemically stable arrangement;

[0151] Z is a carbon atom, —CHR—N—, —HN—CR— or —CHR—CHR—, —O—CHR,—S—CHR, —SO—CHR, —SO₂—CHR, or —N—;

[0152] wherein R is aliphatic, aryl, aralkyl or cycloalkyl;

[0153] R₅ is —(C1-C12) aliphatic, wherein any hydrogen is optionallysubstituted with halogen, and wherein any hydrogen or halogen atom boundto any terminal carbon atom of R₅ is optionally substituted withsulfhydryl or hydroxy;

[0154] W is selected from: —C(O)OH;

[0155] wherein each R₆ is independently:

[0156] hydrogen,

[0157] (C1-C12)-aliphatic,

[0158] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0159] (C6-C10)-aryl,

[0160] (C6-C10)-aryl-(C1-C12)aliphatic,

[0161] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0162] (C3-C10)-heterocyclyl,

[0163] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0164] (C5-C10)heteroaryl, or

[0165] (C5-C10)heteroaryl-(C1-C12)-aliphatic, or

[0166] two R₆ groups, which are bound to the same nitrogen atom, formtogether with that nitrogen atom, a (C3-C10)-heterocyclic ring;

[0167] wherein R₆ is optionally substituted with up to 3 J substituents;

[0168] each R₇ is hydroxy, alkoxy, or aryloxy; or each R₇ is an oxygenatom linked to an aliphatic group and, together with the boron to whichthey are each bound, the two R₇ groups form a 3-6 membered ring;

[0169] V is a bond, —CH(R₈)—, —N(R₈)—, —O—, —O—CH(R₈), —CH(R₈)—O—, —S—,—S—CH(R₈)—, —CH(R₈)—S—, —C(O)—, —C(O)—O—, —O—C(O)—, —C(O)—S—,—C(O)—CHR₈—, —CHR₈—C(O)— —N(R₈)C(O)— —C(O)N(R₈)—, —S(O)—, —S(O)—CH(R₈),—CH(R₈)—S(O)—, —S(O)N(R₈)—, —N(R₈)S(O)—, —S(O)—N(R₈)—CHR₈,—N(R₈)—S(O)—CHR₈—, —CHR₈—S(O)₂, —S(O)₂—CH(R₈)—, —CH(R₈)—S(O)₂—, —S(O)₂N(R₈)—, —N(R₈)—S(O)₂—, —S(O)₂—N(R₈)—CHR₈ or —N(R₈)—S(O)₂—CHR₈;

[0170] wherein R₈ is hydrogen or (C1-C12)-aliphatic;

[0171] T is selected from:

[0172] (C6-C10)-aryl,

[0173] (C6-C10)-aryl-(C1-C12)aliphatic,

[0174] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0175] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0176] (C3-C10)-heterocyclyl,

[0177] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0178] (C5-C10)heteroaryl, or

[0179] (C5-C10)heteroaryl-(C1-C12)-aliphatic; or

[0180] T is selected from:

[0181] wherein:

[0182] R₁₀ is:

[0183] hydrogen,

[0184] (C1-C12)-aliphatic,

[0185] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0186] (C6-C10)-aryl,

[0187] (C6-C10)-aryl-(C1-C12)aliphatic,

[0188] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0189] (C3-C10)-heterocyclyl,

[0190] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0191] (C5-C10)-heteroaryl, or

[0192] (C5-C10)-heteroaryl-(C1-C12)-aliphatic,

[0193] wherein each T is optionally substituted with up to 3 Jsubstituents;

[0194] K is a bond, (C1-C12)-aliphatic, —O—, —S—, —NR₉—, —C(O)—, or—C(O)—NR₉—, wherein R₉ is hydrogen or (C1-C12)-aliphatic; and

[0195] n is 1-3.

[0196] Definitions

[0197] The term “aryl” as used herein means a monocyclic or bicycliccarbocyclic aromatic ring system comprising 6 to 10 atoms. Phenyl is anexample of a monocyclic aromatic ring system. Bicyclic carbocyclicaromatic ring systems include systems wherein both rings are aromatic,e.g., naphthyl, and systems wherein only one of the two rings isaromatic, e.g., tetralin.

[0198] The bond “---” refers to an optionally present bond.

[0199] The term “heterocyclyl” or “heterocyclic” as used herein means a3-10 membered monocyclic or bicyclic non-aromatic ring system having upto 4 heteroatom or heteroatom groups in each ring selected from O, N,NH, S, SO or SO₂ in a chemically stable arrangement. In such a bicyclicnon-aromatic ring system embodiment of “heterocyclyl”:

[0200] both rings may contain said heteroatom or heteroatom groups; or

[0201] one ring may contain said heteroatom or heteroatom groups and theother ring may be a C3-C6 cycloalkyl or phenyl.

[0202] Heterocyclic rings include 3-1H-benzimidazol-2-one,3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino,3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,benzodithiane, and 1,3-dihydro-imidazol-2-one.

[0203] The term “heteroaryl” as used herein means a 5-10 memberedmonocyclic or bicyclic aromatic ring system having up to 4 heteroatom orheteroatom groups in each ring selected from O, N, NH or S in achemically stable arrangement. In such a bicyclic aromatic ring systemembodiment of “heteroaryl”:

[0204] one or both rings may be aromatic;

[0205] both rings may contain said heteroatom or heteroatom groups; or

[0206] one ring may contain said heteroatom or heteroatom groups and theother ring may be a C3-C6 cycloalkyl or phenyl.

[0207] Heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g.,3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g.,5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl,3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl),pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl,pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl,3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl). Each of the above aryl,heterocyclyl or heteroaryl above may contain up to 3 substituentsindependently selected from halogen, —OR′, —NO₂, —CF₃, —OCF₃, —R′, oxo,—OR′, —O-benzyl, —O-phenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy,—N(R′)₂, —C(O)R′, —COOR′ or —CON(R′)₂, wherein R′ is independentlyselected from H, (C1-C6)-alkyl, (C2-C6)-alkenyl or alkynyl.

[0208] The phrase “chemically stable arrangement” as used herein refersto a compound structure that renders the compound sufficiently stable toallow manufacture and administration to a mammal by methods known in theart. Typically, such compounds are stable at a temperature of 40° C. orless, in the absence of moisture or other chemically reactive condition,for at least a week.

[0209] In an alternate embodiment of formulae (I)-(IV), R¹ is—CH₂—CH(CH₃)—CH₃, —C(CH₃)₃, —CH(CH₃)₂, —CH(CH₃)—CH₂—CH₃ or cyclohexyl; Vis —C(O)N(R₈)—, —S(O)N(R₈)—, —S(O)₂N(R₈)—, a bond, —CH(R₈)—, —N(R₈)—,—O—, —O—CH(R₈)—, —S—, —S—CH(R₈), —C(O)—, —C(O)—O—, —C(O)—S—,—C(O)—CHR₈—, —S(O)—, —S(O)—CH(R₈), —S(O)—N(R₈)—CHR₈, —S(O)₂—,—S—(O)₂—CH(R₈)—, or —S(O)₂—N(R₈)—CHR₈; or J is halogen, —OR′, —NO₂,—CF₃, —OCF₃, —R′, oxo, —OR′, —O-benzyl, —O-phenyl, 1,2-methylenedioxy,1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′, —C(O)R′, —COOR′ or—CON(R′)₂, wherein R′ is independently selected from:

[0210] hydrogen,

[0211] (C1-C12)-aliphatic,

[0212] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0213] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0214] (C6-C10)-aryl,

[0215] (C6-C10)-aryl-(C1-C12)aliphatic,

[0216] (C3-C10)-heterocyclyl,

[0217] (C6-C10)-heterocyclyl-(C1-C12)aliphatic,

[0218] (C5-C10)-heteroaryl, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic;

[0219] and the other variables are as defined herein.

[0220] In compounds of formula (I), ring A is preferably selected from:

[0221] wherein R is aliphatic, aryl, aralkyl or cycloalkyl.

[0222] More preferably, ring A is selected from:

[0223] Ring B is preferably selected from:

[0224] wherein R is aliphatic, aryl, aralkyl or cycloalkyl.

[0225] More preferably, ring B is selected from:

[0226] According to another preferred embodiment of compounds of formula(I), rings A, B, together with the ring connected thereto include:

[0227] According to another preferred embodiment, R₁ is selected from—(C1-C10)alkyl, —(C3-C7)cycloalkyl, or—((C1-C6)alkyl)-((C3-C7)cycloalkyl). More preferably, R₁ is selectedfrom:

[0228] Even more preferably, R₁ is selected from —CH₂—C(CH₃)₃, —C(CH₃)₃,—CH(CH₃)₂, —CH(CH₃)—CH₂—CH₃, or cyclohexyl. Most preferably R₁ iscyclohexyl.

[0229] According to another preferred embodiment, R₂ is(C1-C12)-aliphatic. More preferably, R₂ is selected from hydrogen,methyl, ethyl or propyl. Even more preferably, R₂ is hydrogen or methyl.Most preferably, R₂ is hydrogen.

[0230] According to another preferred embodiment, R₃ is selected from—(C1-C10)alkyl, —(C3-C7)cycloalkyl, or—((C1-C6)alkyl)-((C3-C7)cycloalkyl).

[0231] More preferably, R₃ is selected from:

[0232] Even more preferably, R₃ is selected from —C(CH₃)₂, —CH(CH₃)₂,—CH(CH₃)—CH₂—CH₃, or cyclohexyl. Most preferably, R₃ is selected from—C(CH₃)₃ or —CH(CH₃)₂.

[0233] According to another preferred embodiment, R₄ is(C1-C12)-aliphatic. More preferably, R₄ is selected from hydrogen,methyl, ethyl or propyl. Even more preferably, R₄ is selected fromhydrogen.

[0234] According to another preferred embodiment, R₅ is —(C2-C7)alkyloptionally substituted with halogen. Preferably, R₅ is selected from:

[0235] More preferably, R₅ is selected from —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂F, —CH₂CH₂CHF₂, or —CH₂CH₂CF₃. Even more preferably, R₅ isselected from —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃ or —CH₂CH₂CHF₂. Most preferably,R₅ is —CH₂CH₂CH₃ or —CH₂CH₂CH₂CH₃.

[0236] According to another preferred embodiment W is selected from:CHO, —C(O)—R₆, —CO₂H, —C(O)—C(O)—R₆, or —C(O)—C(O)—NH(R₆), wherein R₆ isselected from hydrogen, aryl, heteroaryl, heterocyclyl, C3-C6 alkyl,C3-C6 cycloalkyl, hydroxy, —O—C1-C6 alkyl, wherein —NH(R₆) is selectedfrom —NH—(C3-C6 cycloalkyl), NH-aralkyl, —NH-alkylheteroaryl,—NH-alkylheterocyclyl, and wherein said aryl, heterocyclyl or heteroarylis optionally susbtituted with up to 3 halogen atoms.

[0237] More preferably, R₆ or —NH(R₆) is selected from:

[0238] According to another preferred embodiment W is selected from—C(O)OH or —C(O)—C(O)—R₆. More preferably, W is —C(O)—C(O)—R₆.Preferably, R₆ is isopropyl.

[0239] According to a preferred embodiment, W is —C(O)—C(O)—R₆.Preferably, R₆ is isopropyl.

[0240] According to another preferred embodiment, W is —C(O)—C(O)—OR₆.Preferably, R₆ is hydrogen, (C1-C12)-aliphatic, (C6-C10)-aryl,(C3-C10)-cycloalkyl or -cycloalkenyl, (C3-C10)-heterocyclyl or(C5-C10)heteroaryl. More preferably, R₆ is H or methyl.

[0241] According to yet another preferred embodiment, W is—C(O)—C(O)—N(R₆)₂. Preferably, R₆ is hydrogen, (C3-C10)-cycloalkyl or-cycloalkenyl, or (C3-C10)-heterocyclyl.

[0242] In another preferred embodiment of compounds of formula (I) iswhere W is C(O)—C(O)—N(R₆)₂, the NR₆R₆ portion of the W moiety is—NH—(C3-C6)cycloalkyl, —NH—CH(CH₃)—(C6-C10)aryl or—NH—CH(CH₃)—(C3-C10)heterocyclyl, or —NH—CH(CH₃)—(C5-C10)heteroaryl,wherein said aryl, heterocyclyl, or heteroaryl is optionally substitutedwith halogen.

[0243] Alternatively, the NR₆R₆ portion is —NH—(C3-C6)cycloalkyl,—NH—CH(CH₃)—(C6-C10)aryl, or —NH—CH(CH₃)—(C5-C10)heteroaryl, whereinsaid aryl or said heterocyclyl is optionally substituted with halogen;or NR₆R₆ is —NH—(C3-C6) cycloalkyl, —NH—CH(CH₃)—(C6-C10)aryl, or—NH—CH(CH₃)—(C3-C10)heterocyclyl, wherein said aryl or said heterocyclylis optionally substituted with halogen.

[0244] In other preferred embodiment of formula I, NR₆R₆ in W is:

[0245] More preferably, NR₆R₆ is:

[0246] Even more preferably, NR₆R₆ is:

[0247] Most preferably, NR₆R₆ is:

[0248] According to another preferred embodiment, when W is —B(R₇)₂,each R₇ is selected from hydroxy, alkoxy, or aryloxy.

[0249] According to yet another preferred embodiment, when W is —B(R₇)₂,each R₇ is selected from an oxygen atom linked to an aliphatic groupand, together with the boron to which they are each bound, the two R₇groups form a 5-8 membered ring.

[0250] According to another preferred embodiment, V is a bond, —CH(R₈)—,—N(R₈)—, —O—, —O—CH(R₈), —S—, —S—CH(R₈), —C(O)—, —C(O)—O—, —C(O)—S—,—C(O)—CHR₈—, —C(O)N(R₈)—, —S(O)—, —S(O)—CH(R₈)—, —S(O)N(R₈)—,—S(O)—N(R₈)—CHR₈, —S(O)₂, —S—(O)₂—CH(R₈)—, —S(O)₂N(R₈)—, or—S(O)₂—N(R₈)—CHR₈; wherein R₈ is hydrogen or —(C1-C3)alkyl;

[0251] According to another preferred embodiment, V is —NH—.

[0252] According to yet another preferred embodiment, V is —C(O)—.

[0253] According to yet another preferred embodiment, V is —C(O)—NR₈—.More preferably, V is —C(O)—NH—.

[0254] According to yet another preferred embodiment T is a heterocyclylor heteroaryl, optionally having up to 3 substituents as defined above.

[0255] According to yet another preferred embodiment, T is a—(C5-C10)heteroaryl.

[0256] According to yet another preferred embodiment, T is selected from3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, pyrazolinyl,1,3-dihydro-imidazol-2-one, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrrolyl, 3-pyrrolyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 5-tetrazolyl, pyrazolyl,pyrazinyl or 1,3,5-triazinyl.

[0257] Even more preferably, T is selected from 3-1H-benzimidazol-2-one,3-(1-alkyl)-benzimidazol-2-one, pyrazolinyl, 1,3-dihydro-imidazol-2-one,2-imidazolyl, 2-pyrrolyl, 2-pyrimidinyl, 5-pyrimidinyl, 5-tetrazolyl orpyrazinyl.

[0258] Most preferred is when T or R⁷ is selected from:

[0259] Preferred substituents on T in the above embodiments are halogen,—CF₃, —OCF₃, oxo, —COOR′, or —CON(R′)₂, wherein R′ is as defined above.

[0260] According to another preferred embodiment of this invention, Tcontains at least one hydrogen bond donor moiety selected from —NH₂,—NH—, —OH, and —SH.

[0261] In a preferred embodiment, T is:

[0262] wherein:

[0263] T is optionally substituted with up to 3 J substituents, whereinJ is as defined in claim 1;

[0264] Y is independently O, S, NR₁₀, or C(R₁₀)₂;

[0265] n is independently 1 or 2; and

[0266]

is independently a single bond or a double bond.

[0267] In another preferred embodiment, T is:

[0268] wherein Y is as defined above.

[0269] More preferably T is

[0270] According to yet another preferred embodiment, T is:

[0271] (C6-C10)-aryl,

[0272] (C6-C10)-aryl-(C1-C12)aliphatic,

[0273] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0274] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic,

[0275] (C3-C10)-heterocyclyl,

[0276] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0277] (C5-C10)heteroaryl, or

[0278] (C5-C10)heteroaryl-(C1-C12)-aliphatic,

[0279] wherein each T is optionally substituted with up to 3 Jsubstituents.

[0280] According to yet another preferred embodiment of this invention,T:

[0281] wherein:

[0282] R₁₀ is:

[0283] hydrogen,

[0284] (C1-C12)-aliphatic,

[0285] (C6-C10)-aryl,

[0286] (C6-C10)-aryl-(C1-C12) aliphatic,

[0287] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0288] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic,

[0289] (C3-C10)-heterocyclyl,

[0290] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0291] (C5-C10)heteroaryl, or

[0292] (C5-C10)heteroaryl-(C1-C12)-aliphatic,

[0293] wherein each T is optionally substituted with up to 3 Jsubstituents;

[0294] K is a bond, —O—, —S—, —NR₉—, 13 C(O)—, or —C(O)—NR₉—, wherein R₉is hydrogen or C1-C12 aliphatic; and

[0295] n is 1-3.

[0296] More preferably, T is:

[0297] According to another embodiment, the present invention providescompounds of formula (II):

[0298] wherein:

[0299] ring A is a carbocyclic, heteroaryl or heterocyclic ring, whereinring A is optionally fused to an carbocyclic, heterocyclic or heteroarylring;

[0300] wherein ring A has up to 4 substituents selected independentlyfrom J;

[0301] ring C is a cycloalkyl or heterocyclic ring;

[0302] wherein ring C has up to 3 substituents selected independentlyfrom J;

[0303] J is halogen, —OR′, —NO₂, —CF₃, —OCF₃, —R′, oxo, —O-benzyl,—O-phenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′,—SO₂R′, —C(O)R′, —OC(O)R′, —COOR′ or —CON(R′)₂, wherein R′ isindependently selected from:

[0304] hydrogen,

[0305] (C1-C12)-aliphatic,

[0306] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0307] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0308] (C6-C10)-aryl,

[0309] (C6-C10)-aryl-(C1-C12)aliphatic,

[0310] (C3-C10)-heterocyclyl,

[0311] (C6-C10)-heterocyclyl-(C1-C12)aliphatic,

[0312] (C5-C10)-heteroaryl, or

[0313] (C5-C10)-heteroaryl-(C1-C12)-aliphatic;

[0314] R₁ and R₃ are independently:

[0315] (C1-C12)-aliphatic,

[0316] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0317] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0318] (C6-C10)-aryl,

[0319] (C6-C10)-aryl-(C1-C12)aliphatic,

[0320] (C3-C10)-heterocyclyl,

[0321] (C6-C10)-heterocyclyl-(C1-C12)aliphatic,

[0322] (C5-C10)-heteroaryl, or

[0323] (C5-C10)-heteroaryl-(C1-C12)-aliphatic,

[0324] wherein each of R₁ and R₃ is independently and optionallysubstituted with up to 3 substituents independently selected from J;

[0325] wherein up to 3 aliphatic carbon atoms in R₁ and R₃ may bereplaced by a heteroatom selected from O, NH, S, SO, or SO₂ in achemically stable arrangement;

[0326] R₂ and R₄ are independently

[0327] hydrogen,

[0328] (C1-C12)-aliphatic,

[0329] (C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or

[0330] (C6-C10)aryl-(C1-C12)-aliphatic,

[0331] wherein each of R₂ and R₄ is independently and optionallysubstituted with up to 3 substituents independently selected from J;

[0332] wherein up to two aliphatic carbon atoms in R₂ and R₄ may bereplaced by a heteroatom selected from O, NH, S, SO, or SO₂ in achemically stable arrangement;

[0333] Z is a carbon atom, —CHR—N—, —HN—CR— or —CHR—CHR—, —O—CHR—,—S—CHR—, —SO—CHR—, —SO₂—CHR—, or —N—;

[0334] wherein R is aliphatic, aryl, aralkyl or cycloalkyl;

[0335] R₅ is —(C1-C12) aliphatic, wherein any hydrogen is optionallysubstituted with halogen, and wherein any hydrogen or halogen atom boundto any terminal carbon atom of R₅ is optionally substituted withsulfhydryl or hydroxy;

[0336] W is selected from: —C(O)OH;

[0337] wherein each R₆ is independently:

[0338] hydrogen,

[0339] (C1-C12)-aliphatic,

[0340] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0341] (C6-C10)-aryl,

[0342] (C6-C10)-aryl-(C1-C12)aliphatic,

[0343] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0344] (C3-C10)-heterocyclyl,

[0345] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0346] (C5-C10)heteroaryl, or

[0347] (C5-C10)heteroaryl-(C1-C12)-aliphatic, or

[0348] two R₆ groups, which are bound to the same nitrogen atom, formtogether with that nitrogen atom, a (C3-C10)-heterocyclic ring;

[0349] wherein R₆ is optionally substituted with up to 3 J substituents;

[0350] each R₇ is hydroxy, alkoxy, or aryloxy; or

[0351] each R₇ is an oxygen atom linked to an aliphatic group and,together with the boron to which they are each bound, the two R₇ groupsform a 3-6 membered ring;

[0352] V is a bond, —CH(R₈)—, —N(R₈)—, —O—, —O—CH(R₈), —CH(R₈)—O—, —S—,—S—CH(R₈)—, —CH(R₈)—S—, —C(O)—, —C(O)—O—, —O—C(O)—, —C(O)—S—,—C(O)—CHR₈—, —CHR₈—C(O)—, —N(R₈)C(O)——C(O)N(R₈)—, —S(O)—, —S(O)—CH(R₈),—CH(R₈)—S(O)—, —S(O)N(R₈)—, —N(R₈)S(O)—, —S(O)—N(R₈)—CHR₈,—N(R₈)—S(O)—CHR₈—, —CHR₈—S(O)₂, —S(O)₂—CH(R₈)—, —CH(R₈)—S(O)₂—,—S(O)₂N(R₈)—, —N(R₈)—S(O)₂—, —S(O)₂—N(R₈)—CHR₈ or —N(R₈)—S(O)₂-CHR₈;

[0353] wherein R₈ is hydrogen or (C1-C12)-aliphatic;

[0354] T is selected from:

[0355] (C6-C10)-aryl,

[0356] (C6-C10)-aryl-(C1-C12)aliphatic,

[0357] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0358] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0359] (C3-C10)-heterocyclyl,

[0360] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0361] (C5-C10)heteroaryl, or

[0362] (C5-C10)heteroaryl-(C1-C12)-aliphatic; or

[0363] T is selected from:

[0364] wherein:

[0365] R₁₀ is:

[0366] hydrogen,

[0367] (C1-C12)-aliphatic,

[0368] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0369] (C6-C10)-aryl,

[0370] (C6-C10)-aryl-(C1-C12) aliphatic,

[0371] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0372] (C3-C10)-heterocyclyl,

[0373] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0374] (C5-C10)-heteroaryl, or

[0375] (C5-C10)-heteroaryl-(C1-C12)-aliphatic,

[0376] wherein each T is optionally substituted with up to 3 Jsubstituents;

[0377] K is a bond, (C1-C12)-aliphatic, —O—, —S—, —NR₉—, —C(O)—, or—C(O)—NR₉—, wherein R₉ is hydrogen or (C1-C12)-aliphatic; and

[0378] n is 1-3.

[0379] In compounds of formula (II), ring C is preferably selected from:

[0380] In compounds of formula (II), rings A and C, together with thering that they are attached to, are preferably selected from:

[0381] According to another preferred embodiment, R₁ is selected from—(C1-C10)alkyl, —(C3-C7)cycloalkyl, or—((C1-C6)alkyl)-((C3-C7)cycloalkyl). More preferably, R₁ is selectedfrom:

[0382] Even more preferably, R₁ is selected from —CH₂—C(CH₃)₃, —C(CH₃)₃,—CH(CH₃)₂, —CH(CH₃)—CH₂—CH₃, or cyclohexyl. Most preferably R₁ iscyclohexyl.

[0383] According to another preferred embodiment, R₂ is(C1-C12)-aliphatic. More preferably, R₂ is selected from hydrogen,methyl, ethyl or propyl. Even more preferably, R₂ is hydrogen or methyl.Most preferably, R₂ is hydrogen.

[0384] According to another preferred embodiment, R₃ is selected from—(C1-C10)alkyl, —(C3-C7)cycloalkyl, or—((C1-C6)alkyl)-((C3-C7)cycloalkyl).

[0385] More preferably, R₃ is selected from:

[0386] Even more preferably, R₃ is selected from —C(CH₃)₂, —CH(CH₃)₂,—CH(CH₃)—CH₂—CH₃, or cyclohexyl. Most preferably, R₃ is selected from—C(CH₃)₃ or —CH(CH₃)₂.

[0387] According to another preferred embodiment, R₄ is(C1-C12)-aliphatic. More preferably, R₄ is selected from hydrogen,methyl, ethyl or propyl. Even more preferably, R₄ is selected fromhydrogen.

[0388] According to another preferred embodiment, R₅ is —(C2-C7)alkyloptionally substituted with halogen. Preferably, R₅ is selected from:

[0389] More preferably, R₅ is selected from —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂F, —CH₂CH₂CHF₂, or —CH₂CH₂CF₃. Even more preferably, R₅ isselected from —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃ or —CH₂CH₂CHF₂. Most preferably,R₅ is —CH₂CH₂CH₃ or —CH₂CH₂CH₂CH₃.

[0390] According to another preferred embodiment W is selected from:CHO, —C(O)—R₆, —CO₂H, —C(O)—C(O)—R₆, or —C(O)—C(O)—NH(R₆), wherein R₆ isselected from hydrogen, aryl, heteroaryl, heterocyclyl, C3-C6 alkyl,C3-C6 cycloalkyl, hydroxy, —O—C1-C6 alkyl, wherein —NH(R₆) is selectedfrom —NH—(C3-C6 cycloalkyl), NH-aralkyl, —NH-alkylheteroaryl,—NH-alkylheterocyclyl, and wherein said aryl, heterocyclyl or heteroarylis optionally susbtituted with up to 3 halogen atoms.

[0391] More preferably, R₆ or —NH(R₆) is selected from:

[0392] According to another preferred embodiment W is selected from—C(O)OH or —C(O)—C(O)—R₆. More preferably, W is —C(O)—C(O)—R₆.Preferably, R₆ is isopropyl.

[0393] According to a preferred embodiment, W is —C(O)—C(O)—R₆.Preferably, R₆ is isopropyl.

[0394] According to another preferred embodiment, W is —C(O)—C(O)—OR₆.Preferably, R₆ is hydrogen, (C1-C12)-aliphatic, (C6-C10)-aryl,(C3-C10)-cycloalkyl or -cycloalkenyl, (C3-C10)-heterocyclyl or(C5-C10)heteroaryl. More preferably, R₆ is H or methyl.

[0395] According to yet another preferred embodiment, W is—C(O)—C(O)—N(R₆)₂. Preferably, R₆ is hydrogen, (C3-C10)-cycloalkyl or-cycloalkenyl, or (C3-C10)-heterocyclyl.

[0396] In another preferred embodiment of compounds of formula (II) iswhere W is C(O)—C(O)—N(R₆)₂, the NR₆R₆ portion of the W moiety is—NH—(C3-C6)cycloalkyl, —NH—CH(CH₃)—(C6-C10)aryl or—NH—CH(CH₃)—(C3-C10)heterocyclyl, or —NH—CH(CH₃)—(C5-C10)heteroaryl,wherein said aryl, heterocyclyl, or heteroaryl is optionally substitutedwith halogen.

[0397] Alternatively, the NR₆R₆ portion is —NH—(C3-C6)cycloalkyl,—NH—CH(CH₃)—(C6-C10)aryl, or —NH—CH(CH₃)—(C5-C10)heteroaryl, whereinsaid aryl or said heterocyclyl is optionally substituted with halogen;or NR₆R₆ is —NH—(C3-C6) cycloalkyl, —NH—CH(CH₃)—(C6-C10)aryl, or—NH—CH(CH₃)—(C3-C10)heterocyclyl, wherein said aryl or said heterocyclylis optionally substituted with halogen.

[0398] In other preferred embodiment of formula (II), NR₆R₆ in W is:

[0399] More preferably, NR₆R₆ is:

[0400] Even more preferably, NR₆R₆ is:

[0401] Most preferably, NR₆R₆ is:

[0402] According to another preferred embodiment, when W is —B(R₇)₂,each R₇ is selected from hydroxy, alkoxy, or aryloxy.

[0403] According to yet another preferred embodiment, when W is —B(R₇)₂,each R₇ is selected from an oxygen atom linked to an aliphatic groupand, together with the boron to which they are each bound, the two R₇groups form a 5-8 membered ring.

[0404] According to another preferred embodiment, V is a bond, —CH(R₈)—,—N(R₈)—, —O—, —O—CH(R₈), —S—, —S—CH(R₈), —C(O)—, —C(O)—O—, —C(O)—S—,—C(O)—CHR₈—, —C(O)N(R₈)—, —S(O)—, —S(O) —CH(R₈)—, —S(O)N(R₈)—, —S(O)—N(R₈)—CHR₈, —S(O)₂, —S—(O)₂—CH(R₈)—, —S(O)₂N(R₈)—, or—S(O)₂—N(R₈)—CHR₈; wherein R₈ is hydrogen or —(C1-C3)alkyl;

[0405] According to another preferred embodiment, V is —NH—.

[0406] According to yet another preferred embodiment, V is —C(O)—.

[0407] According to yet another preferred embodiment, V is —C(O)—NR₈—.More preferably, V is —C(O)—NH—.

[0408] According to yet another preferred embodiment T is a heterocyclylor heteroaryl, optionally having up to 3 substituents as defined above.

[0409] According to yet another preferred embodiment, T is a—(C5-C10)heteroaryl.

[0410] According to yet another preferred embodiment, T is selected from3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, pyrazolinyl,1,3-dihydro-imidazol-2-one, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrrolyl, 3-pyrrolyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 5-tetrazolyl, pyrazolyl,pyrazinyl or 1,3,5-triazinyl.

[0411] Even more preferably, T is selected from 3-1H-benzimidazol-2-one,3-(1-alkyl)-benzimidazol-2-one, pyrazolinyl, 1,3-dihydro-imidazol-2-one,2-imidazolyl, 2-pyrrolyl, 2-pyrimidinyl, 5-pyrimidinyl, 5-tetrazolyl orpyrazinyl.

[0412] Most preferred is when T or R⁷ is selected from:

[0413] Preferred substituents on T in the above embodiments are halogen,—CF₃, —OCF₃, oxo, —COOR′, or —CON(R′)₂, wherein R′ is as defined above.

[0414] According to another preferred embodiment of this invention, Tcontains at least one hydrogen bond donor moiety selected from —NH₂,—NH—, —OH, and —SH.

[0415] In a preferred embodiment, T is:

[0416] wherein:

[0417] T is optionally substituted with up to 3 J substituents, whereinJ is as defined in claim 1;

[0418] Y is independently O, S, NR₁₀, O, or C(R₁₀)₂;

[0419] n is independently 1 or 2; and

[0420]

is independently a single bond or a double bond.

[0421] In another preferred embodiment, T is:

[0422] wherein Y is as defined above.

[0423] More preferably T is

[0424] According to yet another preferred embodiment, T is:

[0425] (C6-C10)-aryl,

[0426] (C6-C10)-aryl-(C1-C12)aliphatic,

[0427] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0428] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic,

[0429] (C3-C10)-heterocyclyl,

[0430] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0431] (C5-C10)heteroaryl, or

[0432] (C5-C10)heteroaryl-(C1-C12)-aliphatic,

[0433] wherein each T is optionally substituted with up to 3 Jsubstituents.

[0434] According to yet another preferred embodiment of this invention,T:

[0435] wherein:

[0436] R₁₀ is:

[0437] hydrogen,

[0438] (C1-C12)-aliphatic,

[0439] (C6-C10)-aryl,

[0440] (C6-C10)-aryl-(C1-C12)aliphatic,

[0441] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0442] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic,

[0443] (C3-C10)-heterocyclyl,

[0444] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0445] (C5-C10)heteroaryl, or

[0446] (C5-C10)heteroaryl-(C1-C12)-aliphatic,

[0447] wherein each T is optionally substituted with up to 3 Jsubstituents;

[0448] K is a bond, —O—, —S—, —NR₉—, —C(O)—, or —C(O)—NR₉—, wherein R₉is hydrogen or C1-C12 aliphatic; and

[0449] n is 1-3.

[0450] More preferably, T is:

[0451] According to another embodiment, the present invention providescompounds of formula (III):

[0452] wherein:

[0453] ring B is a carbocyclic or heterocyclic ring, wherein ring B isoptionally fused to a carbocyclic, heterocyclic or heteroaryl ring;

[0454] wherein ring B has up to 3 substituents selected independentlyfrom J;

[0455] ring C is a cycloalkyl or heterocyclic ring;

[0456] wherein ring C has up to 3 substituents selected independentlyfrom J;

[0457] Z is a carbon atom, —CHR—N—, —HN—CR— or —CHR—CHR—;

[0458] wherein, rings B and C are attached to the same carbon atom in Z;or

[0459] rings B and C are attached vicinally to Z when Z is —CHR—N—,—HN—CR— or —CHR—CHR—;

[0460] wherein R is aliphatic, aryl, aralkyl or cycloalkyl;

[0461] J is halogen, —OR′, —NO₂, —CF₃, —OCF₃, —R′, oxo, —O-benzyl,—O-phenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′,—SO₂R′, —C(O)R′, —OC(O)R′, —COOR′ or —CON(R′)₂, wherein R′ isindependently selected from:

[0462] hydrogen,

[0463] (C1-C12)-aliphatic,

[0464] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0465] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0466] (C6-C10)-aryl,

[0467] (C6-C10)-aryl-(C1-C12)aliphatic,

[0468] (C3-C10)-heterocyclyl,

[0469] (C6-C10)-heterocyclyl-(C1-C12)aliphatic,

[0470] (C5-C10)-heteroaryl, or

[0471] (C5-C10)-heteroaryl-(C1-C12)-aliphatic;

[0472] R₁ and R₃ are independently:

[0473] (C1-C12)-aliphatic,

[0474] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0475] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0476] (C6-C10)-aryl,

[0477] (C6-C10)-aryl-(C1-C12)aliphatic,

[0478] (C3-C10)-heterocyclyl,

[0479] (C6-C10)-heterocyclyl-(C1-C12)aliphatic,

[0480] (C5-C10)-heteroaryl, or

[0481] (C5-C10)-heteroaryl-(C1-C12)-aliphatic,

[0482] wherein each of R₁ and R₃ is independently and optionallysubstituted with up to 3 substituents independently selected from J;

[0483] wherein up to 3 aliphatic carbon atoms in R₁ and R₃ may bereplaced by a heteroatom selected from O, NH, S, SO, or SO₂ in achemically stable arrangement;

[0484] R₂ and R₄ are independently

[0485] hydrogen,

[0486] (C1-C12)-aliphatic,

[0487] (C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or

[0488] (C6-C10)aryl-(C1-C12)-aliphatic,

[0489] wherein each of R₂ and R₄ is independently and optionallysubstituted with up to 3 substituents independently selected from J;

[0490] wherein up to two aliphatic carbon atoms in R₂ and R₄ may bereplaced by a heteroatom selected from O, NH, S, SO, or SO₂ in achemically stable arrangement;

[0491] R₅ is —(C1-C12) aliphatic, wherein any hydrogen is optionallysubstituted with halogen, and wherein any hydrogen or halogen atom boundto any terminal carbon atom of R₅ is optionally substituted withsulfhydryl or hydroxy;

[0492] W is selected from: —C(O)OH;

[0493] wherein each R₆ is independently:

[0494] hydrogen,

[0495] (C1-C12)-aliphatic,

[0496] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0497] (C6-C10)-aryl,

[0498] (C6-C10)-aryl-(C1-C12)aliphatic,

[0499] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0500] (C3-C10)-heterocyclyl,

[0501] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0502] (C5-C10)heteroaryl, or

[0503] (C5-C10)heteroaryl-(C1-C12)-aliphatic, or

[0504] two R₆ groups, which are bound to the same nitrogen atom, formtogether with that nitrogen atom, a (C3-C10)-heterocyclic ring;

[0505] wherein R₆ is optionally substituted with up to 3 J substituents;

[0506] each R₇ is hydroxy, alkoxy, or aryloxy; or

[0507] each R₇ is an oxygen atom linked to an aliphatic group and,together with the boron to which they are each bound, the two R₇ groupsform a 3-6 membered ring;

[0508] V is a bond, —CH(R₈)—, —N(R₈)—, —O—, —O—CH(R₈), —CH(R₈)—O—, —S—,—S—CH(R₈)—, —CH(R₈)—S—, —C(O)—, —C(O)—O—, —O—C(O)—, —C(O)—S—,—C(O)—CHR₈—, —CHR₈—C(O)— —N(R₈)C(O)— —C(O)N(R₈)—, —S(O)—, —S(O)—CH(R₈),—CH(R₈)—S(O)—, —S(O)N(R₈)—, —N(R₈)S(O)—, —S(O)—N(R₈)—CHR₈,—N(R₈)—S(O)—CHR₈—, —CHR₈—S(O)₂, —S(O)₂—CH(R₈)—, —CH(R₈)—S(O)₂—,—S(O)₂N(R₈)—, —N(R₈)—S(O)₂, —S(O)₂—N(R₈)—CHR₈ or —N(R₈)—S(O)₂—CHR₈;

[0509] wherein R₈ is hydrogen or (C1-C12)-aliphatic;

[0510] T is selected from:

[0511] (C6-C10)-aryl,

[0512] (C6-C10)-aryl-(C1-C12)aliphatic,

[0513] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0514] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0515] (C3-C10)-heterocyclyl,

[0516] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0517] (C5-C10)heteroaryl, or

[0518] (C5-C10)heteroaryl-(C1-C12)-aliphatic; or

[0519] T is selected from:

[0520] wherein

[0521] R₁₀ is:

[0522] hydrogen

[0523] (C1-C12)-aliphatic

[0524] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0525] (C6-C10)-aryl,

[0526] (C6-C10)-aryl-(C1-C12)aliphatic,

[0527] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0528] (C3-C10)-heterocyclyl,

[0529] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0530] (C5-C10)-heteroaryl, or

[0531] (C5-C10)-heteroaryl-(C1-C12)-aliphatic,

[0532] wherein each T is optionally substituted with up to 3 Jsubstituents;

[0533] K is a bond, (C1-C12)-aliphatic, —O—, —S—, —NR₉—, —C(O)—, or—C(O)—NR₉—, wherein R₉ is hydrogen or (C1-C12)-aliphatic; and

[0534] n is 1-3.

[0535] According to a preferred embodiment, R₁ is selected from—(C1-C10)alkyl, —(C3-C7)cycloalkyl, or—((C1-C6)alkyl)-((C3-C7)cycloalkyl). More preferably, R₁ is selectedfrom:

[0536] Even more preferably, R₁ is selected from —CH₂—C C(CH₃)₃,—C(CH₃)₃, —CH(CH₃)₂, —CH(CH₃)—CH₂—CH₃, or cyclohexyl. Most preferably R₁is cyclohexyl.

[0537] According to another preferred embodiment, R₂ is(C1-C12)-aliphatic. More preferably, R₂ is selected from hydrogen,methyl, ethyl or propyl. Even more preferably, R₂ is hydrogen or methyl.Most preferably, R₂ is hydrogen.

[0538] According to another preferred embodiment, R₃ is selected from—(C1-C10)alkyl, —(C3-C7)cycloalkyl, or—((C1-C6)alkyl)-((C3-C7)cycloalkyl).

[0539] More preferably, R₃ is selected from:

[0540] Even more preferably, R₃ is selected from —C(CH₃)₂, —CH(CH₃)₂,—CH(CH₃)—CH₂—CH₃, or cyclohexyl. Most preferably, R₃ is selected from—C(CH₃)₃ or —CH(CH₃)₂.

[0541] According to another preferred embodiment, R₄ is(C1-C12)-aliphatic. More preferably, R₄ is selected from hydrogen,methyl, ethyl or propyl. Even more preferably, R₄ is selected fromhydrogen.

[0542] According to another preferred embodiment, R₅ is —(C2-C7)alkyloptionally substituted with halogen. Preferably, R₅ is selected from:

[0543] More preferably, R₅ is selected from —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂F, —CH₂CH₂CHF₂, or —CH₂CH₂CF₃. Even more preferably, R₅ isselected from —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃ or —CH₂CH₂CHF₂. Most preferably,R₅ is —CH₂CH₂CH₃ or —CH₂CH₂CH₂CH₃.

[0544] According to another preferred embodiment W is selected from:CHO, —C(O)—R₆, —CO₂H, —C(O)—C(O)—R₆, or —C(O)—C(O)—NH(R₆), wherein R₆ isselected from hydrogen, aryl, heteroaryl, heterocyclyl, C3-C6 alkyl,C3-C6 cycloalkyl, hydroxy, —O—C1-C6 alkyl, wherein —NH(R₆) is selectedfrom —NH—(C3-C6 cycloalkyl), NH-aralkyl, —NH-alkylheteroaryl,—NH-alkylheterocyclyl, and wherein said aryl, heterocyclyl or heteroarylis optionally susbtituted with up to 3 halogen atoms.

[0545] More preferably, R₆ or —NH(R₆) is selected from:

[0546] According to another preferred embodiment W is selected from—C(O)OH or —C(O)—C(O)—R₆. More preferably, W is —C(O)—C(O)—R₆.Preferably, R₆ is isopropyl.

[0547] According to a preferred embodiment, W is —C(O)—C(O)—R₆.Preferably, R₆ is isopropyl.

[0548] According to another preferred embodiment, W is —C(O)—C(O)—OR₆.Preferably, R₆ is hydrogen, (C1-C12)-aliphatic, (C6-C10)-aryl,(C3-C10)-cycloalkyl or -cycloalkenyl, (C3-C10)-heterocyclyl or(C5-C10)heteroaryl. More preferably, R₆ is H or methyl.

[0549] According to yet another preferred embodiment, W is—C(O)—C(O)—N(R₆)₂. Preferably, R₆ is hydrogen, (C3-C10)-cycloalkyl or-cycloalkenyl, or (C3-C10)-heterocyclyl.

[0550] In another preferred embodiment of compounds of formula (III) iswhere W is C(O)—C(O)—N(R₆)₂, the NR₆R₆ portion of the W moiety is—NH—(C3-C6)cycloalkyl, —NH—CH(CH₃)—(C6-C10)aryl or—NH—CH(CH₃)—(C3-C10)heterocyclyl, or —NH—CH(CH₃)—(C5-C10)heteroaryl,wherein said aryl, heterocyclyl, or heteroaryl is optionally substitutedwith halogen.

[0551] Alternatively, the NR₆R₆ portion is —NH—(C3-C6)cycloalkyl,—NH—CH(CH₃)—(C6-C10)aryl, or —NH—CH(CH₃)—(C5-C10)heteroaryl, whereinsaid aryl or said heterocyclyl is optionally substituted with halogen;or NR₆R₆ is —NH—(C3-C6) cycloalkyl, —NH—CH(CH₃)—(C6-C10)aryl, or—NH—CH(CH₃)—(C3-C10)heterocyclyl, wherein said aryl or said heterocyclylis optionally substituted with halogen.

[0552] In other preferred embodiment of formula (III), NR₆R₆ in W is:

[0553] More preferably, NR₆R₆ is:

[0554] Even more preferably, NR₆R₆ is:

[0555] Most preferably, NR₆R₆ is:

[0556] According to another preferred embodiment, when W is —B(R₇)₂,each R₇ is selected from hydroxy, alkoxy, or aryloxy.

[0557] According to yet another preferred embodiment, when W is —B(R₇)₂,each R₇ is selected from an oxygen atom linked to an aliphatic groupand, together with the boron to which they are each bound, the two R₇groups form a 5-8 membered ring.

[0558] According to another preferred embodiment, V is a bond, —CH(R₈)—,—N(R₈)—, —O—, —O—CH(R₈), —S—, —S—CH(R₈), —C(O)—, —C(O)—O—, —C(O)—S—,—C(O)—CHR₈—, —C(O)N(R₈)—, —S(O)—, —S(O)—CH(R₈)—, —S(O)N(R₈)—,—S(O)—N(R₈)—CHR₈, —S(O)₂, —S—(O)₂—CH(R₈)—, —S(O)₂N(R₈)—, or—S(O)₂—N(R₈)—CHR₈; wherein R₈ is hydrogen or —(C1-C3)alkyl;

[0559] According to another preferred embodiment, V is —NH—.

[0560] According to yet another preferred embodiment, V is —C(O)—.

[0561] According to yet another preferred embodiment, V is —C(O)—NR₈—.More preferably, V is —C(O)—NH—.

[0562] According to yet another preferred embodiment T is a heterocyclylor heteroaryl, optionally having up to 3 substituents as defined above.

[0563] According to yet another preferred embodiment, T is a—(C5-C10)heteroaryl.

[0564] According to yet another preferred embodiment, T is selected from3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, pyrazolinyl,1,3-dihydro-imidazol -2-one, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrrolyl, 3-pyrrolyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 5-tetrazolyl, pyrazolyl,pyrazinyl or 1,3,5-triazinyl.

[0565] Even more preferably, T is selected from 3-1H-benzimidazol-2-one,3-(1-alkyl)-benzimidazol-2-one, pyrazolinyl, 1,3-dihydro-imidazol-2-one,2-imidazolyl, 2-pyrrolyl, 2-pyrimidinyl, 5-pyrimidinyl, 5-tetrazolyl orpyrazinyl.

[0566] Most preferred is when T or R⁷ is selected from:

[0567] Preferred substituents on T in the above embodiments are halogen,—CF₃, —OCF₃, oxo, —COOR′, or —CON(R′)₂, wherein R′ is as defined above.

[0568] According to another preferred embodiment of this invention, Tcontains at least one hydrogen bond donor moiety selected from —NH₂,—NH—, —OH, and —SH.

[0569] In a preferred embodiment, T is:

[0570] wherein:

[0571] T is optionally substituted with up to 3 J substituents, whereinJ is as defined in claim 1;

[0572] Y is independently O, S, NR₁₀, or C(R₁₀)₂;

[0573] n is independently 1 or 2; and

[0574]

is independently a single bond or a double bond.

[0575] In another preferred embodiment, T is:

[0576] wherein Y is as defined above.

[0577] More preferably T is

[0578] According to yet another preferred embodiment, T is:

[0579] (C6-C10)-aryl,

[0580] (C6-C10)-aryl-(C1-C12)aliphatic,

[0581] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0582] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic,

[0583] (C3-C10)-heterocyclyl,

[0584] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0585] (C5-C10)heteroaryl, or

[0586] (C5-C10)heteroaryl-(C1-C12)-aliphatic,

[0587] wherein each T is optionally substituted with up to 3 Jsubstituents.

[0588] According to yet another preferred embodiment of this invention,T:

[0589] wherein:

[0590] R₁₀ is:

[0591] hydrogen,

[0592] (C1-C12)-aliphatic,

[0593] (C6-C10)-aryl,

[0594] (C6-C10)-aryl-(C1-C12)aliphatic,

[0595] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0596] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic,

[0597] (C3-C10)-heterocyclyl,

[0598] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0599] (C5-C10)heteroaryl, or

[0600] (C5-C10)heteroaryl-(C1-C12)-aliphatic,

[0601] wherein each T is optionally substituted with up to 3 Jsubstituents;

[0602] K is a bond, —O—, —S—, —NR₉—, —C(O)—, or —C(O)—NR₉—, wherein R₉is hydrogen or C1-C12 aliphatic; and

[0603] n is 1-3.

[0604] More preferably, T is:

[0605] In compounds of formula (III), the preferred embodiments of ringB are as defined for compounds of formula (I).

[0606] In compounds of formula (III), the preferred embodiments of ringC are as defined for compounds of formula (II).

[0607] According to another embodiment, the present invention providescompounds of formula (IV):

[0608] wherein:

[0609] ring B is a bridged bicyclic ring system containing 6-12 carbonatoms, wherein ring B is saturated or partially unsaturated; or

[0610] the ring system comprising ring B, together with the ringcontaining Z and the nitrogen atom, contains more than ten ring atoms;

[0611] wherein ring B has up to 3 substituents selected independentlyfrom J;

[0612] J is halogen, —OR′, —NO₂, —CF₃, —OCF₃, —R′, oxo, —OR′, —O-benzyl,—O-phenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′,—SO₂R′, —C(O)R′, —COOR′ or —CON(R′)₂, wherein R′ is independentlyselected from:

[0613] hydrogen,

[0614] (C1-C12)-aliphatic,

[0615] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0616] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0617] (C6-C10)-aryl,

[0618] (C6-C10)-aryl-(C1-C12)aliphatic,

[0619] (C3-C10)-heterocyclyl,

[0620] (C6-C10)-heterocyclyl-(C1-C12)aliphatic,

[0621] (C5-C10)-heteroaryl, or

[0622] (C5-C10)-heteroaryl-(C1-C12)-aliphatic;

[0623] R₁ and R₃ are independently:

[0624] (C1-C12)-aliphatic,

[0625] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0626] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0627] (C6-C10)-aryl,

[0628] (C6-C10)-aryl-(C1-C12)aliphatic,

[0629] (C3-C10)-heterocyclyl,

[0630] (C6-C10)-heterocyclyl-(C1-C12)aliphatic,

[0631] (C5-C10)-heteroaryl, or

[0632] (C5-C10)-heteroaryl-(C1-C12)-aliphatic,

[0633] wherein each of R₁ and R₃ is independently and optionallysubstituted with up to 3 substituents independently selected from J;

[0634] wherein up to 3 aliphatic carbon atoms in R₁ and R₃ may bereplaced by a heteroatom selected from O, NH, S, SO, or SO₂ in achemically stable arrangement;

[0635] R₂ and R₄ are independently hydrogen,

[0636] (C1-C12)-aliphatic,

[0637] (C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or

[0638] (C6-C10)aryl-(C1-C12)-aliphatic,

[0639] wherein each of R₂ and R₄ is independently and optionallysubstituted with up to 3 substituents independently selected from J;

[0640] wherein up to two aliphatic carbon atoms in R₂ and R₄ may bereplaced by a heteroatom selected from O, NH, S, SO, or SO₂ in achemically stable arrangement;

[0641] Z is a carbon atom, —CHR—N—, —HN—CR— or —CHR—CHR—, —O—CHR—,—S—CHR—, —SO—CHR—, —SO₂—CHR—, or —N—;

[0642] wherein R is aliphatic, aryl, aralkyl or cycloalkyl;

[0643] R₅ is —(C1-C12) aliphatic, wherein any hydrogen is optionallysubstituted with halogen, and wherein any hydrogen or halogen atom boundto any terminal carbon atom of R₅ is optionally substituted withsulfhydryl or hydroxy;

[0644] W is selected from: —C(O)OH;

[0645] wherein each R₆ is independently:

[0646] hydrogen,

[0647] (C1-C12)-aliphatic,

[0648] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0649] (C6-C10)-aryl,

[0650] (C6-C10)-aryl-(C1-C12)aliphatic,

[0651] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0652] (C3-C10)-heterocyclyl,

[0653] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0654] (C5-C10)heteroaryl, or

[0655] (C5-C10)heteroaryl-(C1-C12)-aliphatic, or

[0656] two R₆ groups, which are bound to the same nitrogen atom, formtogether with that nitrogen atom, a (C3-C10)-heterocyclic ring;

[0657] wherein R₆ is optionally substituted with up to 3 J substituents;

[0658] each R₇ is hydroxy, alkoxy, or aryloxy; or

[0659] each R₇ is an oxygen atom linked to an aliphatic group and,together with the boron to which they are each bound, the two R₇ groupsform a 3-6 membered ring;

[0660] V is a bond, —CH(R₈)—, —N(R₈)—, —O—, —O—CH(R₈), —CH(R₈)—O—, —S—,—S—CH(R₈)—, —CH(R₈)—S—, —C(O)—, —C(O)—O—, —O—C(O)—, —C(O)—S—,—C(O)—CHR₈—, —CHR₈—C(O)— —N(R₈)C(O)— —C(O)N(R₈)—, —S(O)—, —S(O)—CH(R₈),—CH(R₈)—S(O)—, —S(O)N(R₈)—, —N(R₈)S(O)—, —S(O)—N(R₈)—CHR₈,—N(R₈)—S(O)—CHR₈—, —CHR₈—S(O)₂, —S(O)₂—CH(R₈)—, —CH(R₈)—S(O)₂—,—S(O)₂N(R₈)—, —N(R₈)—S(O)₂—, —S(O)₂—N(R₈)—CHR₈ or —N(R₈)—S(O)₂—CHR₈;

[0661] wherein R₈ is hydrogen or (C1-C12)-aliphatic;

[0662] T is selected from:

[0663] (C6-C10)-aryl,

[0664] (C6-C10)-aryl-(C1-C12)aliphatic,

[0665] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0666] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0667] (C3-C10)-heterocyclyl,

[0668] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0669] (C5-C10)heteroaryl, or

[0670] (C5-C10)heteroaryl-(C1-C12)-aliphatic; or

[0671] T is selected from:

[0672] wherein:

[0673] R₁₀ is:

[0674] hydrogen,

[0675] (C1-C12)-aliphatic,

[0676] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],

[0677] (C6-C10)-aryl,

[0678] (C6-C10)-aryl-(C1-C12)aliphatic,

[0679] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0680] (C3-C10)-heterocyclyl,

[0681] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0682] (C5-C10)-heteroaryl, or

[0683] (C5-C10)-heteroaryl-(C1-C12)-aliphatic,

[0684] wherein each T is optionally substituted with up to 3 Jsubstituents;

[0685] K is a bond, (C1-C12)-aliphatic, —O—, —S—, —NR₉—, —C(O)—, or—C(O)—NR₉—, wherein R₉ is hydrogen or (C1-C12)-aliphatic; and

[0686] n is 1-3.

[0687] According to a preferred embodiment of compounds of formula (IV),ring B is a bridged bicyclic ring system containing 6-12 carbon atoms,wherein ring B is saturated or partially unsaturated, and ring B has upto 3 substituents selected independently from J.

[0688] Preferred embodiments of ring B in compound of formula (IV)include:

[0689] According to a preferred embodiment, R₁ is selected from—(C1-C10)alkyl, —(C3-C7)cycloalkyl, or—((C1-C6)alkyl)-((C3-C7)cycloalkyl). More preferably, R₁ is selectedfrom:

[0690] Even more preferably, R₁ is selected from —CH₂—C C(CH₃)₃,—C(CH₃)₃, —CH(CH₃)₂, —CH(CH₃)—CH₂—CH₃, or cyclohexyl. Most preferably R₁is cyclohexyl.

[0691] According to another preferred embodiment, R₂ is(C1-C12)-aliphatic. More preferably, R₂ is selected from hydrogen,methyl, ethyl or propyl. Even more preferably, R₂ is hydrogen or methyl.Most preferably, R₂ is hydrogen.

[0692] According to another preferred embodiment, R₃ is selected from—(C1-C10)alkyl, —(C3-C7)cycloalkyl, or—((C1-C6)alkyl)-((C3-C7)cycloalkyl).

[0693] More preferably, R₃ is selected from:

[0694] Even more preferably, R₃ is selected from —C(CH₃)₂, —CH(CH₃)₂,—CH(CH₃)—CH₂—CH₃, or cyclohexyl. Most preferably, R₃ is selected from—C(CH₃)₃ or —CH(CH₃)₂.

[0695] According to another preferred embodiment, R₄ is(C1-C12)-aliphatic. More preferably, R₄ is selected from hydrogen,methyl, ethyl or propyl. Even more preferably, R₄ is selected fromhydrogen.

[0696] According to another preferred embodiment, R₅ is —(C2-C7)alkyloptionally substituted with halogen. Preferably, R₅ is selected from:

[0697] More preferably, R₅ is selected from —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂F, —CH₂CH₂CHF₂, or —CH₂CH₂CF₃. Even more preferably, R₅ isselected from —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃ or —CH₂CH₂CHF₂. Most preferably,R₅ is —CH₂CH₂CH₃ or —CH₂CH₂CH₂CH₃.

[0698] According to another preferred embodiment W is selected from:CHO, —C(O)—R₆, —CO₂H, —C(O)—C(O)—R₆, or —C(O)—C(O)—NH(R₆), wherein R₆ isselected from hydrogen, aryl, heteroaryl, heterocyclyl, C3-C6 alkyl,C3-C6 cycloalkyl, hydroxy, —O—C1-C6 alkyl, wherein —NH(R₆) is selectedfrom —NH—(C3-C6 cycloalkyl), NH-aralkyl, —NH-alkylheteroaryl,—NH-alkylheterocyclyl, and wherein said aryl, heterocyclyl or heteroarylis optionally substituted with up to 3 halogen atoms.

[0699] More preferably, R₆ or —NH(R₆) is selected from:

[0700] According to another preferred embodiment W is selected from—C(O)OH or —C(O)—C(O)—R₆. More preferably, W is —C(O)—C(O)—R₆.Preferably, R₆ is isopropyl.

[0701] According to a preferred embodiment, W is —C(O)—C(O)—R₆.Preferably, R₆ is isopropyl.

[0702] According to another preferred embodiment, W is —C(O)—C(O)—OR₆.Preferably, R₆ is hydrogen, (C1-C12)-aliphatic, (C6-C10)-aryl,(C3-C10)-cycloalkyl or -cycloalkenyl, (C3-C10)-heterocyclyl or(C5-C10)heteroaryl. More preferably, R₆ is H or methyl.

[0703] According to yet another preferred embodiment, W is—C(O)—C(O)—N(R₆)₂. Preferably, R₆ is hydrogen, (C3-C10)-cycloalkyl or-cycloalkenyl, or (C3-C10)-heterocyclyl.

[0704] In another preferred embodiment of compounds of formula (IV) iswhere W is C(O)—C(O)—N(R₆)₂, the NR₆R₆ portion of the W moiety is—NH—(C3-C6)cycloalkyl, —NH—CH(CH₃)—(C6-C10)aryl or—NH—CH(CH₃)—(C3-C10)heterocyclyl, or —NH—CH(CH₃)—(C5-C10)heteroaryl,wherein said aryl, heterocyclyl, or heteroaryl is optionally substitutedwith halogen.

[0705] Alternatively, the NR₆R₆ portion is —NH—(C3-C6)cycloalkyl,—NH—CH(CH₃)—(C6-C10)aryl, or —NH—CH(CH₃)—(C5-C10)heteroaryl, whereinsaid aryl or said heterocyclyl is optionally substituted with halogen;or NR₆R₆ is —NH—(C3-C6) cycloalkyl, —NH—CH(CH₃)—(C6-C10)aryl, or—NH—CH(CH₃)—(C3-C10)heterocyclyl, wherein said aryl or said heterocyclylis optionally substituted with halogen.

[0706] In other preferred embodiment of formula I, NR₆R₆ in W is:

[0707] More preferably, NR₆R₆ is:

[0708] Even more preferably, NR₆R₆ is:

[0709] Most preferably, NR₆R₆ is:

[0710] According to another preferred embodiment, when W is —B(R₇)₂,each R₇ is selected from hydroxy, alkoxy, or aryloxy.

[0711] According to yet another preferred embodiment, when W is —B(R₇)₂,each R₇ is selected from an oxygen atom linked to an aliphatic groupand, together with the boron to which they are each bound, the two R₇groups form a 5-8 membered ring.

[0712] According to another preferred embodiment, V is a bond, —CH(R₈)—,—N(R₈)—, —O—, —O—CH(R₈), —S—, —S—CH(R₈), —C(O)—, —C(O)—O—, —C(O)—S—,—C(O)—CHR₈—, —C(O)N(R₈)—, —S(O)—, —S(O)—CH(R₈)—, —S(O)N(R₈)—,—S(O)—N(R₈)—CHR₈, —S(O)₂, —S—(O)₂—CH(R₈)—, —S(O)₂N(R₈)—, or—S(O)₂—N(R₈)—CHR₈)—CHR₈; wherein R₈ is hydrogen or —(C1-C3)alkyl;

[0713] According to another preferred embodiment, V is —NH—.

[0714] According to yet another preferred embodiment, V is —C(O)—.

[0715] According to yet another preferred embodiment, V is —C(O)—NR₈—.More preferably, V is —C(O)—NH—.

[0716] According to yet another preferred embodiment T is a heterocyclylor heteroaryl, optionally having up to 3 substituents as defined above.

[0717] According to yet another preferred embodiment, T is a—(C5-C10)heteroaryl.

[0718] According to yet another preferred embodiment, T is selected from3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, pyrazolinyl,1,3-dihydro-imidazol -2-one, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrrolyl, 3-pyrrolyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 5-tetrazolyl, pyrazolyl,pyrazinyl or 1,3,5-triazinyl.

[0719] Even more preferably, T is selected from 3-1H-benzimidazol-2-one,3-(1-alkyl)-benzimidazol-2-one, pyrazolinyl, 1,3-dihydro-imidazol-2-one,2-imidazolyl, 2-pyrrolyl, 2-pyrimidinyl, 5-pyrimidinyl, 5-tetrazolyl orpyrazinyl.

[0720] Most preferred is when T or R⁷ is selected from:

[0721] Preferred substituents on T in the above embodiments are halogen,—CF₃, —OCF₃, oxo, —COOR′, or —CON(R′)₂, wherein R′ is as defined above.

[0722] According to another preferred embodiment of this invention, Tcontains at least one hydrogen bond donor moiety selected from —NH₂,—NH—, —OH, and —SH.

[0723] In a preferred embodiment, T is:

[0724] wherein:

[0725] T is optionally substituted with up to 3 J substituents, whereinJ is as defined in claim 1;

[0726] Y is independently O, S, NR₁₀, or C(R₁₀)₂;

[0727] n is independently 1 or 2; and

[0728]

is independently a single bond or a double bond.

[0729] In another preferred embodiment, T is:

[0730] wherein Y is as defined above.

[0731] More preferably T is

[0732] According to yet another preferred embodiment, T is:

[0733] (C6-C10)-aryl,

[0734] (C6-C10)-aryl-(C1-C12)aliphatic,

[0735] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0736] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic,

[0737] (C3-C10)-heterocyclyl,

[0738] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0739] (C5-C10)heteroaryl, or

[0740] (C5-C10)heteroaryl-(C1-C12)-aliphatic,

[0741] wherein each T is optionally substituted with up to 3 Jsubstituents.

[0742] According to yet another preferred embodiment of this invention,T:

[0743] wherein:

[0744] R₁₀ is:

[0745] hydrogen,

[0746] (C1-C12)-aliphatic,

[0747] (C6-C10)-aryl,

[0748] (C6-C10)-aryl-(C1-C12)aliphatic,

[0749] (C3-C10)-cycloalkyl or -cycloalkenyl,

[0750] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic,

[0751] (C3-C10)-heterocyclyl,

[0752] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,

[0753] (C5-C10)heteroaryl, or

[0754] (C5-C10)heteroaryl-(C1-C12)-aliphatic,

[0755] wherein each T is optionally substituted with up to 3 Jsubstituents;

[0756] K is a bond, —O—, —S—, —NR₉—, —C(O)—, or —C(O)—NR₉—, wherein R₉is hydrogen or C1-C12 aliphatic; and n is 1-3.

[0757] More preferably, T is:

[0758] The compounds of this invention may contain one or moreasymmetric carbon atoms and thus may occur as racemates and racemicmixtures, single enantiomers, diastereomeric mixtures and individualdiastereomers. All such isomeric forms of these compounds are expresslyincluded in the present invention. Each stereogenic carbon may be of theR or S configuration.

[0759] More preferably, the compounds of this invention have thestructure and stereochemistry depicted below in generalized formula (V):

[0760] wherein T, R, R₃ and R₆ represent the embodiments set forth aboveand rings A, B, and C, if present, represent the embodiments set forthfor compounds of formulas (I), (II), (III), and (IV).

[0761] Any of the preferred embodiments recited above may be combined toproduce a preferred embodiment of this invention.

[0762] The compounds of this invention may be synthesized by standardchemical schemes well-known in the art. Schemes 1-22 below illustratesynthetic routes to the compounds of the present invention. Otherequivalent schemes, which will be readily apparent to the ordinaryskilled organic chemist, may alternatively be used to synthesize variousportions of the molecule. A more specific synthetic scheme for compound1A within applicants' invention is set forth in the examples.

[0763] Preparation of Compounds of Formula (I)

[0764] Preparation of Compounds of Formula (I)

[0765] Preparation of Compounds of Formula (I)

[0766] Preparation of Compounds of Formula (I)

[0767] Preparation of Compounds of Formula (II)

[0768] Preparation of Compounds of Formula (IV)

[0769] Preparation of Compounds of Formula (IV)

[0770] Preparation of Compounds of Formula (IV)

[0771] Preparation of Compounds of Formula (IV)

[0772] Preparation of Compounds of Formula (IV)

[0773] Preparation of Compounds of Formula (IV)

[0774] Preparation of Compounds of Formula (IV)

[0775] Preparation of Compounds of Formula (IV)

[0776] Preparation of Compounds of Formula (III)

[0777] Compounds 1 to 26 and compound 1A in Schemes 1-15, 19-22illustrate the multicyclic core of the peptidomimetic compounds of thepresent invention. These cores are readily converted into the compoundsof the present invention by methods well known in the art.

[0778] For example, compounds 1 to 8 in Schemes 1-7 illustrate the corein compounds of formula (I). Compound 1, e.g., can be converted into acompound of formula (I) using the methods of, e.g., Schemes 16-18.

[0779] Compounds 9-12 in Scheme 8 illustrate the cores in compounds offormula (II). Compounds 9 to 12 can be readily converted into compoundsof formula (II) using the methods of, e.g., Schemes 16-18.

[0780] Compounds 13 and 14 in Scheme 9 illustrate the cores in compoundsof formula (IV). Compounds 13 and 14 can be readily converted intocompounds of formula (IV) using the methods of, e.g., Schemes 16-18.

[0781] Compound 26 in Scheme 21 illustrates the core in compounds offormula (III). Compound 26 can be readily converted into a compound offormula (III) using the methods of, e.g., Schemes 16-18.

[0782] One of skill in the art will readily appreciate that the methodsof Schemes 1-22 can be readily applied to any other ring or ring systemwithin the scope of the present invention. Thus, Schemes 1-22 provide afacile synthetic route to the compounds of the present invention.

[0783] As set forth above, the compounds of this invention are capableof inhibiting the activity of HCV NS3-NS4A protease. In order toquantitate the activity of the compounds of this invention, cellscontaining HCV replicon were incubated with the compounds of thisinvention, and a Taqman Real Time PCR assay was conducted to determinethe percentage inhibition of HCV RNA level and the IC₅₀ were calculatedtherefrom. The results are shown below in Table 1: TABLE 1 Cmpd. Ki IC₅₀No. Structure (nM) (nM) 1A

39 202

[0784] Another embodiment of this invention provides a compositioncomprising a compound of formula (I), formula (II), formula (III), orformula (IV) or a pharmaceutically acceptable salt thereof in an amounteffective to decrease the viral load in a sample or in a patient,wherein said virus encodes a serine protease necessary for the virallife cycle, and a pharmaceutically acceptable carrier.

[0785] If pharmaceutically acceptable salts of the compounds of thisinvention are utilized in these compositions, those salts are preferablyderived from inorganic or organic acids and bases. Included among suchacid salts are the following: acetate, adipate, alginate, aspartate,benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate,camphor sulfonate, cyclopentane-propionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.Base salts include ammonium salts, alkali metal salts, such as sodiumand potassium salts, alkaline earth metal salts, such as calcium andmagnesium salts, salts with organic bases, such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth.

[0786] Also, the basic nitrogen-containing groups may be quaternizedwith such agents as lower alkyl halides, such as methyl, ethyl, propyl,and butyl chloride, bromides and iodides; dialkyl sulfates, such asdimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides suchas decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides,aralkyl halides, such as benzyl and phenethyl bromides and others. Wateror oil-soluble or dispersible products are thereby obtained.

[0787] The compounds utilized in the compositions and methods of thisinvention may also be modified by appending appropriate functionalitiesto enhance selective biological properties. Such modifications are knownin the art and include those which increase biological penetration intoa given biological system (e.g., blood, lymphatic system, centralnervous system), increase oral availability, increase solubility toallow administration by injection, alter metabolism and alter rate ofexcretion.

[0788] Pharmaceutically acceptable carriers that may be used in thesecompositions include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid,potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

[0789] According to a preferred embodiment, the compositions of thisinvention are formulated for pharmaceutical administration to a mammal,preferably a human being.

[0790] Such pharmaceutical compositions of the present invention may beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir.The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. Preferably, the compositions are administeredorally or intravenously.

[0791] Sterile injectable forms of the compositions of this inventionmay be aqueous or oleaginous suspension. These suspensions may beformulated according to techniques known in the art using suitabledispersing or wetting agents and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents which arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms mayalso be used for the purposes of formulation.

[0792] Dosage levels of between about 0.01 and about 100 mg/kg bodyweight per day, preferably between about 0.5 and about 75 mg/kg bodyweight per day of the protease inhibitor compounds described herein areuseful in a monotherapy for the prevention and treatment of antiviral,particularly anti-HCV mediated disease. Typically, the pharmaceuticalcompositions of this invention will be administered from about 1 toabout 5 times per day or alternatively, as a continuous infusion. Suchadministration can be used as a chronic or acute therapy. The amount ofactive ingredient that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Preferably,such preparations contain from about 20% to about 80% active compound.

[0793] When the compositions of this invention comprise a combination ofa compound of formula I, II, III or IV, and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 10 to 100%,and more preferably between about 10 to 80% of the dosage normallyadministered in a monotherapy regimen.

[0794] The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers that are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried cornstarch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

[0795] Alternatively, the pharmaceutical compositions of this inventionmay be administered in the form of suppositories for rectaladministration. These may be prepared by mixing the agent with asuitable non-irritating excipient which is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

[0796] The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

[0797] Topical application for the lower intestinal tract may beeffected in a rectal suppository formulation (see above) or in asuitable enema formulation. Topically-transdermal patches may also beused.

[0798] For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions may be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

[0799] For ophthalmic use, the pharmaceutical compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterilesaline, or, preferably, as solutions in isotonic, pH adjusted sterilesaline, either with our without a preservative such as benzylalkoniumchloride. Alternatively, for ophthalmic uses, the pharmaceuticalcompositions may be formulated in an ointment such as petrolatum.

[0800] The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

[0801] Most preferred are pharmaceutical compositions formulated fororal administration.

[0802] In a related embodiment, the compositions of this inventionadditionally comprise another anti-viral agent, preferably an anti-HCVagent. Such anti-viral agents include, but are not limited to,immunomodulatory agents, such as α-, β-, and γ-interferons and pegylatedderivatized interferon-α compounds; other anti-viral agents, such asribavirin and amantadine; other inhibitors of hepatitis C proteases(NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors of othertargets in the HCV life cycle, including helicase and polymeraseinhibitors; inhibitors of internal ribosome entry; broad-spectrum viralinhibitors, such as IMPDH inhibitors (e.g., VX-497 and other IMPDHinhibitors disclosed in U.S. Pat. No. 5,807,876, mycophenolic acid andderivatives thereof); or combinations of any of the above.

[0803] Upon improvement of a patient's condition, a maintenance dose ofa compound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease.Patients may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

[0804] It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of active ingredients will also depend upon the particulardescribed compound and the presence or absence and the nature of theadditional anti-viral agent in the composition.

[0805] According to another embodiment, the invention provides a methodfor treating a patient infected with a virus characterized by a virallyencoded serine protease that is necessary for the life cycle of thevirus by administering to said patient a pharmaceutically acceptablecomposition of this invention. Preferably, the methods of this inventionare used to treat a patient suffering from a HCV infection. Suchtreatment may completely eradicate the viral infection or reduce theseverity thereof. More preferably, the patient is a human being.

[0806] In an alternate embodiment, the methods of this inventionadditionally comprise the step of administering to said patient ananti-viral agent preferably an anti-HCV agent. Such anti-viral agentsinclude, but are not limited to, immunomodulatory agents, such as α-,β-, and γ-interferons and pegylated derivatized interferon-α compounds;other anti-viral agents, such as ribavirin and amantadine; otherinhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4Ainhibitors); inhibitors of other targets in the HCV life cycle,including helicase and polymerase inhibitors; inhibitors of internalribosome entry; broad-spectrum viral inhibitors, such as IMPDHinhibitors (e.g., VX-497 and other IMPDH inhibitors disclosed in U.S.Pat. No. 5,807,876, mycophenolic acid and derivatives thereof); orcombinations of any of the above.

[0807] Such additional agent may be administered to said patient as partof a single dosage form comprising both a compound of this invention andan additional anti-viral agent. Alternatively the additional agent maybe administered separately from the compound of this invention, as partof a multiple dosage form, wherein said additional agent is administeredprior to, together with or following a composition comprising a compoundof this invention.

[0808] In yet another embodiment the present invention provides a methodof pre-treating a biological substance intended for administration to apatient comprising the step of contacting said biological substance witha pharmaceutically acceptable composition comprising a compound of thisinvention. Such biological substances include, but are not limited to,blood and components thereof such as plasma, platelets, subpopulationsof blood cells and the like; organs such as kidney, liver, heart, lung,etc; sperm and ova; bone marrow and components thereof, and other fluidsto be infused into a patient such as saline, dextrose, etc.

[0809] According to another embodiment the invention provides methods oftreating materials that may potentially come into contact with a viruscharacterized by a virally encoded serine protease necessary for itslife cycle. This method comprises the step of contacting said materialwith a compound according to the invention. Such materials include, butare not limited to, surgical instruments and garments; laboratoryinstruments and garments; blood collection apparatuses and materials;and invasive devices, such as shunts, stents, etc.

[0810] In another embodiment, the compounds of this invention may beused as laboratory tools to aid in the isolation of a virally encodedserine protease. This method comprises the steps of providing a compoundof this invention attached to a solid support; contacting said solidsupport with a sample containing a viral serine protease underconditions that cause said protease to bind to said solid support; andeluting said serine protease from said solid support. Preferably, theviral serine protease isolated by this method is HCV NS3-NS4A protease.

[0811] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any way.

EXAMPLE 13-(tert-Butyl-dimethyl-silanyloxymethyl)-5-oxo-4-aza-tricyclo[5.2.1.0^(2,6)]dec-8-ene-4-carboxylicacid tert-butyl ester (28)

[0812]2-(tert-Butyl-dimethyl-silanyloxymethyl)-5-oxo-2,5-dihydro-pyrrole-1-carboxylicacid tert-butyl ester (27) (4 g; 12.2 mmol) and freshly distilledcyclopentadiene (8 mL; 12 eq.) were heated in a sealed tube in toluenefor 6 h at 110° C. Concentration and purification by flashchromatography (10% EtOAc/90% hexanes) afforded 3.23 g (67%) of thedesired product 28. ¹H NMR (CDCl₃) □.6.1 (bs, 1H), 6.0 (bs, 1H), 3.8(dd, 1H), 3.6 (d, 1H), 3.5 (s, 1H), 3.3 (s, 1H), 3.1 (dd, 1H), 2.9 (s,1H), 2.6 (bs, 1H), 1.6 (d, 2H), 1.5 (s, 9H), 1.3 (d, 1H), 0.9 (s, 9H),0.15 (s, 3H), 0.1 (s, 3H)ppm.

EXAMPLE 23-Hydroxymethyl-5-oxo-4-aza-tricyclo[5.2.1.0^(2,6)]dec-8-ene-4-carboxylicacid tert-butyl ester (29)

[0813] A solution of 28 (3.2 g; 8.1 mmol) in 60 mL of THF and aceticacid (1.16 mL; 20.3 mmol) was treated with TBAF 1M in THF. The reactionmixture was stirred for 16 h then was diluted with CH₂Cl₂ (120 mL) andwashed with water (75 mL). The organic layer was dried with sodiumsulfate and concentrated in vacuo to a yellow oil. Flash chromatography(60% EtOAc/40% hexanes) afforded 1.81 g (81%) of the desired product 29.¹H NMR (CDCl₃) δ6.2 (bs, 1H), 6.1 (bs, 1H), 3.8 (d, 1H), 3.6 (m, 2H),3.3 (s, 1H), 3.15 (dd, 1H), 3.1 (s, 1H), 2.5 (dd, 1H), 1.5 (app.t, 3H),1.35 (s, 9H)ppm.

EXAMPLE 3 3-Hydroxymethyl-4-aza-tricycloc-4-carboxylic acid benzyl ester(32)

[0814] To a solution of 29 (1.81 g, 6.5 mmol) in 50 mL of dry ethylacetate at 0° C. was bubbled dry HCl gas for 5 minutes. Stirring wascontinued while warming up to room temperature over a period of 10minutes. Concentration to dryness afforded a solid residue that wassubjected to lithium aluminium hydride reduction (2.5 equivalents) inrefluxing THF for 2 h. Fieser work up afforded 1.07 g of the reducedproduct 31 that was used directly for the next step. A solution of 31(1.07 g, 6.5 mmol) in 10 mL of dry THF was added to a vigorously stirredsolution of potassium carbonate in 4 mL of water at −2° C. to 0° C.Cbz-Cl was added dropwise maintaining the temperature around 0° C. Afterthe addition was completed (10 minutes), the reaction was furtherstirred for an additional 15 minutes at 0° C. and poured onto crushedice and water (14 mL). Sodium chloride was added to saturate the aqueousphase. The organic phase was separated and the aqueous further extracted(3×50 mL) with ethyl acetate. The combined organic phase was washed with5% aqueous HCl, water and brine, dried (Na₂SO₄) and concentrated invacuo to give, after flash chromatography (50% EtOAc/50% hexanes) 960 mg(50%) of desired product 32. ¹H NMR (CDCl₃) δ7.3 (m, 5H), 6.2 (M, 2H),5.1 (m, 2H), 3.8 (m, 2H), 3.4 (m, 2H), 3.0 (m, 3H), 2.5 (m, 2H), 1.3 (m,2H)ppm.

EXAMPLE 4 4-Aza-tricyclo[5.2.1.0^(2,6)]dec-8-ene-3,4-dicarboxylic acid4-benzyl ester 3-tert-butyl ester (34)

[0815] Compound 32 (410 mg, 1.37 mmol) was dissolved in 5 mL of acetoneand added dropwise to a stirred solution of Jones reagent (1.1 mL) in 1mL of acetone at 0° C. The reaction mixture was stirred at 5° C. for 3 hand was concentrated in vacuo to a dark residue. Residue wasre-dissolved in ethyl acetate (50 mL) and washed (5×10 mL). The organicphase dried (Na₂SO₄) and concentrated in vacuo to give 400 mg (93%) ofcompound 33 that was used directly for the next step. To a solution of33 (400 mg, 1.28 mmol) in 10 mL of CH₂Cl₂ containing a catalytic amountof concentrated sulfuric acid at −20° C. was condensed 2 mL ofisobutylene. The tube was sealed and stirred at room temperature for 60h. The excess isobutylene was released and the CH₂Cl₂ removed in vacuoto a residue that was subjected to after flash chromatography (20%EtOAc/80% hexanes) which gave 378 mg (80%) of the desired ester 34. ¹HNMR (CDCl₃) δ7.3 (m, 5H), 6.2 (m, 2H), 5.0 (m, 2H), 3.8 (m, 1H), 3.5 (m,1H), 3.2 (m, 1H), 3.1 (m, 1H), 2.8 (m, 3H), 1.5 (m, 2H), 1.2 (m, 9H)ppm.

EXAMPLE 5 4-(2-{2-Cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimethyl-butyryl)-4-aza-tricyclo[5.2.1.0^(2,6)]dec-8-ene-3-carboxylic acid tert-butylester (35)

[0816] Removal of the Cbz group of 34 (378 mg, 1.02 mmol) withhydrogenation under 1 atm of hydrogen using Pd-C10% in ethanol gave,after 5 h, the desired aminoester intermediate in quantitative yield.

[0817] The crude compound was coupled to tert-butylglycine shown in thenext step. To a solution of Cbz-tert-butyl glycine (271 mg, 1.02 mmol)in 2 mL of CH₂Cl₂ at 0° C. was added EDC (235 mg, 1.23 mmol), HOBt (203mg, 1.33 mmol) and DIEA (0.534 mL, 3.07 mmol). The resulting mixture wasstirred at 0° C. for 15 min. after which, the above amino ester wasslowly added in 2 mL of CH₂Cl₂. The resulting reaction mixture wasstirred at room temp. for 16 h. Concentration gave a residue that wasre-dissolved in EtOAc. Successive washes with 0.5N HCL, saturatedaqueous NaHCO₃ and brine gave after drying (Na₂SO₄) and concentration invacuo the desired product. Flash chromatography (20% EtOAc/80% hexanes)provided 480 mg (100%) of pure dipeptide. The Cbz group of the dipeptidewas removed as described above and the resulting aminoester dipeptidewas coupled to Cbz-cyclohexyl glycine shown in the next step.

[0818] To a solution of Cbz-cyclohexyl glycine (289 mg, 1 mmol) in 2 mLof CH₂Cl₂ at 0° C. was added EDC (228 mg, 1.19 mmol), HOBt (190 mg, 1.29mmol) and DIEA (0.517 mL, 2.97 mmol). The resulting mixture was stirredat 0° C. for 15 min. after which, the above amino ester was slowly addedin 2 mL of CH₂Cl₂. The resulting reaction mixture was stirred at roomtemp. for 16 h. Concentration gave a residue that was re-dissolved inEtOAc. Successive washes with 0.5N HCL, satd' aqueous NaHCO₃ and brinegave after drying (Na₂SO₄) and concentration in vacuo the desiredproduct which was subjected to flash chromatography (20% EtOAc/80%hexanes) to provide 556 mg (90%) of pure tripeptide. The Cbz group ofthe tripeptide was removed as described above and the resultingaminoester tripeptide was coupled to 1,4-pyrazine carboxylic acid shownin the next step.

[0819] To a solution of 1,4-pyrazine carboxylic acid (110 mg, 0.891mmol) in 2 mL of CH₂Cl₂ was added PyBrOP (457 mg, 0.98 mmol and DIEA(0.465 mL, 2.67 mmol). The resulting mixture was stirred at room temp.for 15 min. after which, the above amino ester was slowly added in 2 mLof CH₂Cl₂. The resulting reaction mixture was stirred at room temp. for16 h. Concentration gave a residue that was re-dissolved in EtOAc.Successive washes with 0.5N HCL, satd' aqueous NaHCO₃ and brine gaveafter drying (Na₂SO₄) and concentration in vacuo the desired productwhich was subjected to flash chromatography (50% EtOAc/50% hexanes) toprovide 410 mg (79%) of pure capped tripeptide 35. ¹H NMR (CDCl₃) δ9.3(s, 1H), 8.8 (s, 1H), 8.5 (s, 1H), 8.3 (d, 1H), 6.7 (d, 1H), 4.9 (d,1H), 4.7 (s, 1H), 4.5 (tr, 1H), 3.95 (d, 1H), 3.6 (app. dd, 1H), 2.6 (m,2H), 2.3 (d, 2H), 1.75 (m, 5H), 1.5 to 0.9 (m, 12H), 1.4 (s, 9H), 1.0(s, 9H)ppm.

EXAMPLE 6 4-(2-{2-Cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimethyl-butyryl)-4-aza-tricyclo[5.2.1.0^(2,6)]dec-8-ene-3-carboxylic acid(1-cycloproylaminooxalyl-butyl)-amide (1A)

[0820] The t-butyl ester group of the capped tripeptide 35 (410 mg,0.688 mmol) was cleaved with a 1:1 mixture of TFA-CH₂Cl₂ at room temp.for 45 minutes and concentrated in vacuo. The resulting aminoesterdipeptide was coupled to hydroxyamide 36 shown in the next step.

[0821] To a stirring solution of the capped tripeptide acid in 6 mL ofdry DMF at 0° C. was added, PyBOP (376 mg, 0.722 mmol) followed by NMM(0.226 mL, 2.06 mmol). The reaction mixture was stirred for 1 h at roomtemp. after which a solution of 36 (168 mg, 0.758 mmol) and 0.226 mL ofNMM was slowly added. The coupling reaction was stirred for 16 hours,diluted with ethyl acetate and was successively washed with; water (3×),citric acid 10%, water and brine. The organic layer was dried (Na₂SO₄)and concentrated in vacuo. Flash chromatography (2.5% MeOH/97.5% ethylacetate) provided 362 mg of hydroxy amide tetrapeptide that was oxidizedwith Dess-Martin periodinane reagent (650 mg, 1.53 mmol) and t-butanol(0.65 mL) in 5 mL of CH₂Cl₂ at room temp. for 3 hours. The reactionmixture was quenched with sodium thiosulfate 1M solution (2 mL) andstirred until the two phases were clearly separated. The organic layerwas diluted with 5 more mL of CH₂Cl₂ and washed (3×) with 10% potassiumcarbonate aqueous solution (5 mL), dried (Na₂SO₄) and concentrated invacuo. Flash chromatography (2.5% MeOH/97.5% ethyl acetate) provided 270mg of ketoamide tetrapeptide 1A. LCMS M+H=706.42, M−H=704.42. RetentionTime (10-90% MeCN—H₂O with 0.1% TFA over 6 minutes)=3.94 min.

EXAMPLE 7

[0822] Cells containing hepatitis C virus (HCV) replicon were maintainedin DMEM containing 10% fetal bovine serum (FBS), 0.25 mg per ml of G418,with appropriate supplements (media A).

[0823] On day 1, replicon cell monolayer was treated with a trypsin:EDTAmixture, removed, and then dilutedh media A into a final concentrationof 100,000 cells per ml wit. 10,000 cells in 100 ul are plated into eachwell of a 96-well tissue culture plate, and culture overnight in atissue culture incubator at 37° C.

[0824] On day 2, compounds (in 100% DMSO) were serially diluted intoDMEM containing 2% FBS, 0.5% DMSO, with appropriate supplements (mediaB). The final concentration of DMSO was maintained at 0.5% throughoutthe dilution series.

[0825] The media on the replicon cell monolayer was removed, and thenmedia B containing various concentrations of compounds was added. MediaB without any compound was added to other wells as no compound controls.

[0826] Cells were incubated with compound or 0.5% DMSO in media B for 48hours in a tissue culture incubator at 37° C.

[0827] At the end of the 48-hour incubation, the media was removed, andthe replicon cell monolayer was washed once with PBS and stored at −80°C. prior to RNA extraction.

[0828] Culture plates with treated replicon cell monolayers were thawed,and a fixed amount of another RNA virus, such as Bovine Viral DiarrheaVirus (BVDV) was added to cells in each well. RNA extraction reagents(such as reagents from RNeasy kits) were added to the cells immediatelyto avoid degradation of RNA. Total RNA was extracted according theinstruction of manufacturer with modification to improve extractionefficiency and consistency. Finally, total cellular RNA, including HCVreplicon RNA, was eluted and stored at −80° C. until further processing.

[0829] A Taqman real-time RT-PCR quantification assay was set up withtwo sets of specific primers and probe. One was for HCV and the otherwas for BVDV. Total RNA extractants from treated HCV replicon cells wereadded to the PCR reactions for quantification of both HCV and BVDV RNAin the same PCR well. Experimental failure was flagged and rejectedbased on the level of BVDV RNA in each well. The level of HCV RNA ineach well was calculated according to a standard curve that is run inthe same PCR plate. The percentage of inhibition or decrease of HCV RNAlevel due to compound treatment was calculated using the DMSO or nocompound control as 0% of inhibition. The IC50 (concentration at which50% inhibition of HCV RNA level is observed) was calculated from thetitration curve of any given compound.

[0830] The IC50 values inhibitory activity of some of the compounds ofthe present invention is shown in Table 1 above.

EXAMPLE 8

[0831] The Ki determinations were performed as follows. The Ki valuesfor some compounds of the present invention are recited above in Table1.

[0832] HPLC Microbore Method for Separation of 5AB Substrate andProducts Substrate

[0833] NH₂-Glu-Asp-Val-Val-(alpha)Abu-Cys-Ser-Met-Ser-Tyr-COOH Stocksolution of 20 mM 5AB was made in DMSO w/0.2M DTT.

[0834] This was stored in aliquots at −20 C.

[0835] Buffer: 50 mM HEPES, pH 7.8; 20% glycerol; 100 mM NaCl Totalassay volume was 200 μL X1 Conc. in (μL) assay Buffer 155 see above 5 mMKK4A 1 25 μM 1 M DTT 1 5 mM DMSO or inhibitor 3 1.5% v/v 0.25 μM tNS3 2025 nM 200 μM 5AB 20 20 μM (initiate)

[0836] The buffer was combined with KK4A, DTT, and tNS3; 177 μL of thissolution was distributed each into wells of 96 well plate and incubatedat 30° C. for ˜5-10 min.

[0837] 3 μL of appropriate concentration of test compound dissolved inDMSO (DMSO only for control) was added to each well and incubate at 30°C. for 15 min.

[0838] Reaction was initiated by addition of 20 μL of 200 μM 5ABsubstrate (20 μM concentration is equivalent or slightly lower than theKm for 5AB) and incubated for 20 min at 30° C. The reaction wasterminated by addition of 50 μL of 10% TFA 200 μL aliquots weretransferred to HPLC vials The SMSY product was isolated from substrateand KK4A by the method which follows.

[0839] Microbore Separation Method

[0840] Instrumentation:

[0841] Hewlett Packard 1100

[0842] Degasser G1322A

[0843] Binary pump G1312A

[0844] Autosampler G1313A

[0845] Column themostated chamber G1316A

[0846] Diode array detector G1315A

[0847] Column: Phenomenex Jupiter; 5 micron C18; 300 angstroms; 150×2mm; P/O 00F-4053-B0

[0848] Column thermostat: 40° C.

[0849] Injection volume: 100 μL

[0850] Solvent A=HPLC grade water+0.1% TFA

[0851] Solvent B=HPLC grade acetonitrile+0.1% TFA Time Flow Max (min) %B (ml/min) press. 0 5 0.2 400 12 60 0.2 400 13 100 0.2 400 16 100 0.2400 17 5 0.2 400

What is claimed is:
 1. A compound of formula (I):

wherein: ring A is a carbocyclic or heterocyclic ring, wherein ring A isoptionally fused to a carbocyclic, heterocyclic or heteroaryl ring;wherein ring A has up to 3 substituents selected independently from J;ring B is a carbocyclic or heterocyclic ring, wherein ring B isoptionally fused to a carbocyclic, heterocyclic or heteroaryl ring;wherein ring B has up to 3 substituents selected independently from J; Jis halogen, —OR′, —NO₂, —CF₃, —OCF₃, —R′, oxo, —OR′, —O-benzyl,—O-phenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′,—SO₂R′, —C(O)R′, —COOR′ or —CON(R′)₂, wherein R′ is independentlyselected from: hydrogen, (C1-C12)-aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or-cycloalkenyl], (C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic,(C3-C10)-heterocyclyl, (C6-C10)-heterocyclyl-(C1-C12)aliphatic,(C5-C10)-heteroaryl, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic; R₁ andR₃ are independently: (C1-C12)-aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or-cycloalkenyl], (C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic,(C3-C10)-heterocyclyl, (C6-C10)-heterocyclyl-(C1-C12)aliphatic,(C5-C10)-heteroaryl, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic, whereineach of R₁ and R₃ is independently and optionally substituted with up to3 substituents independently selected from J; wherein up to 3 aliphaticcarbon atoms in R₁ and R₃ may be replaced by a heteroatom selected fromO, NH, S, SO, or SO₂ in a chemically stable arrangement; R₂ and R₄ areindependently hydrogen, (C1-C12)-aliphatic,(C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or(C6-C10)aryl-(C1-C12)-aliphatic, wherein each of R₂ and R₄ isindependently and optionally substituted with up to 3 substituentsindependently selected from J; wherein up to two aliphatic carbon atomsin R₂ and R₄ may be replaced by a heteroatom selected from O, NH, S, SO,or SO₂ in a chemically stable arrangement; Z is a carbon atom, —CHR—N—,—HN—CR— or —CHR—CHR—, —O—CHR, —S—CHR, —SO—CHR, —SO₂—CHR, or —N—; whereinR is aliphatic, aryl, aralkyl or cycloalkyl; R₅ is —(C1-C12) aliphatic,wherein any hydrogen is optionally substituted with halogen, and whereinany hydrogen or halogen atom bound to any terminal carbon atom of R₅ isoptionally substituted with sulfhydryl or hydroxy; W is selected from:—C(O)OH;

wherein each R₆ is independently: hydrogen, (C1-C12)-aliphatic,(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C3-C10)-heterocyclyl,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)heteroaryl, or(C5-C10)heteroaryl-(C1-C12)-aliphatic, or two R₆ groups, which are boundto the same nitrogen atom, form together with that nitrogen atom, a(C3-C10)-heterocyclic ring; wherein R₆ is optionally substituted with upto 3 J substituents; each R₇ is hydroxy, alkoxy, or aryloxy; or each R₇is an oxygen atom linked to an aliphatic group and, together with theboron to which they are each bound, the two R₇ groups form a 3-6membered ring; V is a bond, —CH(R₈)—, —N(R₈)—, —O—, —O—CH(R₈),—CH(R₈)—O—, —S—, —S—CH(R₈)—, —CH(R₈)—S—, —C(O)—, —C(O)—O—, —O—C(O)—,—C(O)—S—, —C(O)—CHR₈—, —CHR₈—C(O)— —N(R₈)C(O)— —C(O)N(R₈)—, —S(O)—,—S(O)—CH(R₈), —CH(R₈)—S(O)—, —S(O)N(R₈)—, —N(R₈)S(O)—, —S(O)—N(R₈)—CHR₈,—N(R₈)—S(O)—CHR₈—, —CHR₈—S(O)₂, —S(O)₂—CH(R₈)—, —CH(R₈)—S(O)₂—,—S(O)₂N(R₈)—, —N(R₈)—S(O)₂—, —S(O)₂—N(R₈)—CHR₈or —N(R₈)—S(O)₂—CHR₈;wherein R₈ is hydrogen or (C1-C12)-aliphatic; T is selected from:(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or-cycloalkenyl], (C3-C10)-heterocyclyl,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)heteroaryl, or(C5-C10)heteroaryl-(C1-C12)-aliphatic; or T is selected from:

 wherein: R₁₀ is: hydrogen, (C1-C12) -aliphatic, (C1-C12)-aliphatic-[(C3-C10) -cycloalkyl or -cycloalkenyl], (C6-C10) -aryl,(C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl or -cycloalkenyl,(C3-C10)-heterocyclyl, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,(C5-C10)-heteroaryl, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic, whereineach T is optionally substituted with up to 3 J substituents; K is abond, (C1-C12)-aliphatic, —O—, —S—, —NR₉—, —C(O)—, or —C(O)—NR₉—,wherein R₉ is hydrogen or (C1-C12)-aliphatic; and n is 1-3.
 2. Acompound of formula (II):

wherein: ring A is a carbocyclic, heteroaryl or heterocyclic ring,wherein ring A is optionally fused to an carbocyclic, heterocyclic orheteroaryl ring; wherein ring A has up to 4 substituents selectedindependently from J; ring C is a cycloalkyl or heterocyclic ring;wherein ring C has up to 3 substituents selected independently from J; Jis halogen, —OR′, —NO₂, —CF₃, —OCF₃, —R′, oxo, —OR′, —O-benzyl,—O-phenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′,—SO₂R′, —C(O)R′, —COOR′ or —CON(R′)₂, wherein R′ is independentlyselected from: hydrogen, (C1-C12)-aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or-cycloalkenyl], (C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic,(C3-C10)-heterocyclyl, (C6-C10)-heterocyclyl-(C1-C12)aliphatic,(C5-C10)-heteroaryl, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic; R₁ andR₃ are independently: (C1-C12)-aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or-cycloalkenyl], (C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic,(C3-C10)-heterocyclyl, (C6-C10)-heterocyclyl-(C1-C12)aliphatic,(C5-C10)-heteroaryl, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic, whereineach of R₁ and R₃ is independently and optionally substituted with up to3 substituents independently selected from J; wherein up to 3 aliphaticcarbon atoms in R₁ and R₃ may be replaced by a heteroatom selected fromO, NH, S, SO, or SO₂ in a chemically stable arrangement; R₂ and R₄ areindependently hydrogen, (C1-C12)-aliphatic,(C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or(C6-C10)aryl-(C1-C12)-aliphatic, wherein each of R₂ and R₄ isindependently and optionally substituted with up to 3 substituentsindependently selected from J; wherein up to two aliphatic carbon atomsin R₂ and R₄ may be replaced by a heteroatom selected from O, NH, S, SO,or SO₂ in a chemically stable arrangement; Z is a carbon atom, —CHR—N—,—HN—CR— or —CHR—CHR—, —O—CHR, —S—CHR, —SO—CHR, —SO₂—CHR, or —N—; whereinR is aliphatic, aryl, aralkyl or cycloalkyl; R₅ is —(C1-C12) aliphatic,wherein any hydrogen is optionally substituted with halogen, and whereinany hydrogen or halogen atom bound to any terminal carbon atom of R₅ isoptionally substituted with sulfhydryl or hydroxy; W is selected from:—C(O)OH;

wherein each R₆ is independently: hydrogen, (C1-C12)-aliphatic,(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C3-C10)-heterocyclyl,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)heteroaryl, or(C5-C10)heteroaryl-(C1-C12)-aliphatic, or two R₆ groups, which are boundto the same nitrogen atom, form together with that nitrogen atom, a(C3-C10)-heterocyclic ring; wherein R₆ is optionally substituted with upto 3 J substituents; each R₇ is hydroxy, alkoxy, or aryloxy; or each R₇is an oxygen atom linked to an aliphatic group and, together with theboron to which they are each bound, the two R₇ groups form a 3-6membered ring; V is a bond, —CH(R₈)—, —N(R₈)—, —O—, —O—CH(R₈),—CH(R₈)—O—, —S—, —S—CH(R₈)—, —CH(R₈)—S—, —C(O)—, —C(O)—O—, —O—C(O)—,—C(O)—S—, —C(O)—CHR₈—, —CHR₈—C(O)— —N(R₈)C(O)——C(O)N(R₈)—, —S(O)—,—S(O)—CH(R₈), —CH(R₈)—S(O)—, —S(O)N(R₈)—, —N(R₈)S(O)—, —S(O)—N(R₈)—CHR₈,—N(R₈)—S(O)—CHR₈—, —CHR₈—S(O)₂, —S(O)₂—CH(R₈)—, —CH(R₈)—S(O)₂—,—S(O)₂N(R₈)—, —N(R₈)—S(O)₂—, —S(O)₂—N(R₈)—CHR₈ or —N(R₈)—S(O)₂—CHR₈;wherein R₈ is hydrogen or (C1-C12)-aliphatic; T is selected from:(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or-cycloalkenyl], (C3-C10)-heterocyclyl,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)heteroaryl, or(C5-C10)heteroaryl-(C1-C12)-aliphatic; or T is selected from:

 wherein: R₁₀ is: hydrogen, (C1-C12)-aliphatic,(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl], (C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C3-C10)-heterocyclyl,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)-heteroaryl, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic, wherein each T is optionallysubstituted with up to 3 J substituents; K is a bond,(C1-C12)-aliphatic, —O—, —S—, —NR₉—, —C(O)—, or —C(O)—NR₉—, wherein R₉is hydrogen or (C1-C12)-aliphatic; and n is 1-3.
 3. A compound offormula (III):

wherein: ring B is a carbocyclic or heterocyclic ring, wherein ring B isoptionally fused to a carbocyclic, heterocyclic or heteroaryl ring;wherein ring B has up to 3 substituents selected independently from J;ring C is a cycloalkyl or heterocyclic ring; wherein ring C has up to 3substituents selected independently from J; Z is a carbon atom, —CHR—N—,—HN—CR— or —CHR—CHR—; wherein, rings B and C are attached to the samecarbon atom in Z; or rings B and C are attached vicinally to Z when Z is—CHR—N—, —HN—CR— or —CHR—CHR—; wherein R is aliphatic, aryl, aralkyl orcycloalkyl; J is halogen, —OR′, —NO₂, —CF₃, —OCF₃, —R′, oxo, —OR′,—O-benzyl, —O-phenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂,—SR′, —SOR′, —SO₂R′, —C(O)R′, —COOR′ or —CON(R′)₂, wherein R′ isindependently selected from: hydrogen, (C1-C12)-aliphatic,(C3-C10)-cycloalkyl or -cycloalkenyl,(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-heterocyclyl,(C6-C10)-heterocyclyl-(C1-C12)aliphatic, (C5-C10)-heteroaryl, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic; R₁ and R₃ are independently:(C1-C12)-aliphatic, (C3-C10)-cycloalkyl or -cycloalkenyl,(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-heterocyclyl,(C6-C10)-heterocyclyl-(C1-C12)aliphatic, (C5-C10)-heteroaryl, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic, wherein each of R₁ and R₃ isindependently and optionally substituted with up to 3 substituentsindependently selected from J; wherein up to 3 aliphatic carbon atoms inR₁ and R₃ may be replaced by a heteroatom selected from O, NH, S, SO, orSO₂ in a chemically stable arrangement; R₂ and R₄ are independentlyhydrogen, (C1-C12)-aliphatic, (C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or(C6-C10)aryl-(C1-C12)-aliphatic, wherein each of R₂ and R₄ isindependently and optionally substituted with up to 3 substituentsindependently selected from J; wherein up to two aliphatic carbon atomsin R₂ and R₄ may be replaced by a heteroatom selected from O, NH, S, SO,or SO₂ in a chemically stable arrangement; R₅ is —(C1-C12) aliphatic,wherein any hydrogen is optionally substituted with halogen, and whereinany hydrogen or halogen atom bound to any terminal carbon atom of R₅ isoptionally substituted with sulfhydryl or hydroxy; W is selected from:—C(O)OH;

wherein each R₆ is independently: hydrogen, (C1-C12)-aliphatic,(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C3-C10)-heterocyclyl,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)heteroaryl, or(C5-C10)heteroaryl-(C1-C12)-aliphatic, or two R₆ groups, which are boundto the same nitrogen atom, form together with that nitrogen atom, a(C3-C10)-heterocyclic ring; wherein R₆ is optionally substituted with upto 3 J substituents; each R₇ is hydroxy, alkoxy, or aryloxy; or each R₇is an oxygen atom linked to an aliphatic group and, together with theboron to which they are each bound, the two R₇ groups form a 3-6membered ring; V is a bond, —CH(R₈)—, —N(R₈)—, —O—, —O—CH(R₈),—CH(R₈)—O—, —S—, —S—CH(R₈)—, —CH(R₈)—S—, —C(O)—, —C(O)—O—, —O—C(O)—,—C(O)—S—, —C(O)—CHR₈—, —CHR₈—C(O)— —N(R₈)C(O)— —C(O)N(R₈)—, —S(O)—,—S(O)—CH(R₈), —CH(R₈)—S(O)—, —S(O)N(R₈)—, —N(R₈)S(O)—, —S(O)—N(R₈)—CHR₈,—N(R₈)—S(O)—CHR₈—, —CHR₈—S(O)₂, —S(O)₂—CH(R₈)—, —CH(R₈)—S(O)₂—,—S(O)₂N(R₈)—, —N(R₈)—S(O)₂—, —S(O)₂—N(R₈)—CHR₈ or —N(R₈)—S(O)₂—CHR₈;wherein R₈ is hydrogen or (C1-C12)-aliphatic; T is selected from:(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or-cycloalkenyl], (C3-C10)-heterocyclyl,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)heteroaryl, or(C5-C10)heteroaryl-(C1-C12)-aliphatic; or T is selected from:

 wherein: R₁₀ is: hydrogen, (C1-C12)-aliphatic,(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C3-C10)-heterocyclyl,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)-heteroaryl, or COOR′or —CON(R′)₂, wherein R′ is independently selected from: hydrogen,(C1-C12)-aliphatic, (C3-C10)-cycloalkyl or -cycloalkenyl,(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-heterocyclyl,(C6-C10)-heterocyclyl-(C1-C12)aliphatic, (C5-C10)-heteroaryl, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic; R₁ and R₃ are independently:(C1-C12)-aliphatic, (C3-C10)-cycloalkyl or -cycloalkenyl,(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-heterocyclyl,(C6-C10)-heterocyclyl-(C1-C12)aliphatic, (C5-C10)-heteroaryl, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic, wherein each of R₁ and R₃ isindependently and optionally substituted with up to 3 substituentsindependently selected from J; wherein up to 3 aliphatic carbon atoms inR₁ and R₃ may be replaced by a heteroatom selected from O, NH, S, SO, orSO₂ in a chemically stable arrangement; R₂ and R₄ are independentlyhydrogen, (C1-C12)-aliphatic, (C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or(C6-C10)aryl-(C1-C12)-aliphatic, wherein each of R₂ and R₄ isindependently and optionally substituted with up to 3 substituentsindependently selected from J; wherein up to two aliphatic carbon atomsin R₂ and R₄ may be replaced by a heteroatom selected from O, NH, S, SO,or SO₂ in a chemically stable arrangement; Z is a carbon atom, —CHR—N—,—HN—CR— or —CHR—CHR—, —O—CHR, —S—CHR, —SO—CHR, —SO₂—CHR, or —N—; whereinR is aliphatic, aryl, aralkyl or cycloalkyl; R₅ is —(C1-C12) aliphatic,wherein any hydrogen is optionally substituted with halogen, and whereinany hydrogen or halogen atom bound to any terminal carbon atom of R₅ isoptionally substituted with sulfhydryl or hydroxy; W is selected from:—C(O)OH;

wherein each R₆ is independently: hydrogen, (C1-C12)-aliphatic,(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C3-C10)-heterocyclyl,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)heteroaryl, or(C5-C10)heteroaryl-(C1-C12)-aliphatic, or two R₆ groups, which are boundto the same nitrogen atom, form together with that nitrogen atom, a(C3-C10)-heterocyclic ring; wherein R₆ is optionally substituted with upto 3 J substituents; each R₇ is hydroxy, alkoxy, or aryloxy; or each R₇is an oxygen atom linked to an aliphatic group and, together with theboron to which they are each bound, the two R₇ groups form a 3-6membered ring; V is a bond, —CH(R₈)—, —N(R₈)—, —O—, —O—CH(R₈),—CH(R₈)—O—, —S—, —S—CH(R₈)—, —CH(R₈)—S—, —C(O)—, —C(O)—O—, —O—C(O)—,—C(O)—S—, —C(O)—CHR₈—, —CHR₈—C(O)— —N(R₈)C(O)——C(O)N(R₈)—, —S(O)—,—S(O)—CH(R₈), —CH(R₈)—S(O)—, —S(O)N(R₈)—, —N(R₈)S(O)—, —S(O)—N(R₈)—CHR₈,—N(R₈)—S(O)—CHR₈—, —CHR₈—S(O)₂, —S(O)₂—CH(R₈)—, —CH(R₈)—S(O)₂—,—S(O)₂N(R₈)—, —N(R₈)—S(O)₂—, —S(O)₂—N(R₈)—CHR₈ or —N(R₈)—S(O)₂—CHR₈;wherein R₈ is hydrogen or (C1-C12)-aliphatic; T is selected from:(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or-cycloalkenyl], (C3-C10)-heterocyclyl,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)heteroaryl, or(C5-C10)heteroaryl-(C1-C12)-aliphatic; or T is selected from:

 wherein: R₁₀ is: hydrogen, (C1-C12)-aliphatic,(C5-C10)-heteroaryl-(C1-C12)-aliphatic, wherein each T is optionallysubstituted with up to 3 J substituents; K is a bond,(C1-C12)-aliphatic, —O—, —S—, —NR₉—, —C(O)—, or —C(O)—NR₉—, wherein R₉is hydrogen or (C1-C12)-aliphatic; and n is 1-3.
 4. A compound offormula (IV):

wherein: ring B is a bridged bicyclic ring system containing 6-12 carbonatoms, wherein ring B is saturated or partially unsaturated; or the ringsystem comprising ring B, together with the ring containing Z and thenitrogen atom, contains more than ten ring atoms; wherein ring B has upto 3 substituents selected independently from J; J is halogen, —OR′,—NO₂, —CF₃, —OCF₃, —R′, oxo, —OR′, —O-benzyl, —O-phenyl,1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′,—C(O)R′, —(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl or-cycloalkenyl, (C3-C10)-heterocyclyl,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)-heteroaryl, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic, wherein each T is optionallysubstituted with up to 3 J substituents; K is a bond,(C1-C12)-aliphatic, —O—, —S—, —NR₉—, —C(O)—, or —C(O)—NR₉—, wherein R₉is hydrogen or (C1-C12)-aliphatic; and n is 1-3.
 5. The compoundaccording to any one of claims 1-4, wherein: R₅ is —(C2-C7)alkyloptionally substituted with halogen; R₂ and R₄ are independently(C1-C12)-aliphatic; R₃ and R₁ are independently —(C1-C10)alkyl,—(C3-C7)cycloalkyl, or —((C1-C6)alkyl)—((C3-C7)cycloalkyl); V is a bond,—CH(R₈)—, —N(R₈)—, —O—, —O—CH(R₈), —S—, —S—CH(R₈), —C(O)—, —C(O)—O—,—C(O)—S—, —C(O)—CHR₈—, —C(O)N(R₈)—, —S(O)—, —S(O)—CH(R₈)—, —S(O)N(R₈)—,—S(O)—N(R₈)—CHR₈, —S(O)₂, —S—(O)₂—CH(R₈)—, —S(O)₂N(R₈)—, or—S(O)₂—N(R₈)—CHR₈; wherein R₈ is hydrogen or —(C1-C3)alkyl; T is—(C6-C10)aryl, —(C5-C10)heteroaryl, —(C3-C6)cycloalkyl,—(C3-C10)heterocyclyl, —(C1-C6)alkyl-(C6-10)aryl,—(C1-C6)alkyl-(C5-C10)heteroaryl, —(C1-C6)alkyl-(C3-C6)cycloalkyl,—(C1-C6)alkyl-(C3-C10)heterocyclyl, —(C2-C6)alkenyl-(C6-C10)aryl,—(C2-C6)alkenyl-(C5-C10)heteroaryl, —(C2-C6)alkenyl-(C3-C6)cycloalkyl,—(C2-C6)alkenyl-(C3-C10)heterocyclyl,

 wherein: R₁₀ is —(C1-C4)alkyl; W is —C(O)OH, —C(O)—C(O)—R₆, or—C(O)—C(O)—NH (R₆) wherein: R₆ is —(C1-C6)alkyl, —(C6-C10)aryl,—(C3-C6)cycloalkyl, —(C5-C10)heteroaryl, —(C3-C10)heterocyclyl,—NH—((C1-C6)alkyl), —NH—((C3-C6)cycloalkyl), —NH—CH(CH₃)-aryl,—NH—CH(CH₃)—(C5-C10)heteroaryl or —NH—CH(CH₃)—(C3-C10)heterocyclyl,wherein said aryl, heteroaryl, or heterocyclyl is optionally substitutedwith a suitable electron withdrawing group.
 6. The compound according toclaim 5, wherein V is —NH—.
 7. The compound according to claim 5,wherein V is —C(O)—.
 8. The compound according to claim 5, wherein T isa —(C5-C10)heteroaryl.
 9. The compound according to claim 8, wherein Tis:


10. The compound according to claim 5, wherein T contains at least onehydrogen bond donor moiety selected from —NH₂, —NH—, —OH, and —SH. 11.The compound according to claim 10, wherein T is:

wherein: T is optionally substituted with up to 3 J substituents,wherein J is as defined in claim 1; Z is independently O, S, NR₁₀, orC(R₁₀)₂; n is independently 1 or 2; and

is independently a single bond or a double bond.
 12. The compoundaccording to claim 11, wherein T is:


13. The compound according to claim 5, wherein T is:


14. The compound according to claim 13, wherein T is:


15. The compound according to claim 5, wherein R₁ is:


16. The compound according to claim 15, wherein R₁ is —CH₂—C(CH₃)₃,—C(CH₃)₃, —CH(CH₃)₂, —CH(CH₃)—CH₂—CH₃, or cyclohexyl.
 17. The compoundaccording to claim 16, wherein R₁ is cyclohexyl.
 18. The compoundaccording to claim 5, wherein R₃ is:


19. The compound according to claim 18, wherein R₃ is —C(CH₃)₂,—CH(CH₃)₂, —CH(CH₃)—CH₂—CH₃, or cyclohexyl.
 20. The compound accordingto claim 19, wherein R₃ is —C(CH₃)₃ or —CH(CH₃)₂.
 21. The compoundaccording to claim 5, wherein R₅ is:


22. The compound according to claim 21, wherein R₅ is —CH₂CH₂CH₃,—CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂F, —CH₂CH₂CHF₂, or —CH₂CH₂CF₃.
 23. The compoundaccording to claim 22, wherein R₅ is —CH₂CH₂CH₂CH₃ or —CH₂CH₂CHF₂. 24.The compound according to claim 23, wherein R₅ is —CH₂CH₂CH₂CH₃.
 25. Thecompound according to claim 5, wherein R₂ and R₄ are each independentlyH, methyl, ethyl, or propyl.
 26. The compound according to claim 5,wherein W is C(O)—C(O)—NH(R₆).
 27. The compound according to claim 26,wherein in the W, the —NH(R₆) is —NH—(C₃-C₆ cycloalkyl),—NH—CH(CH₃)-aryl, or —NH—CH(CH₃)-heterocyclyl, wherein said aryl or saidheterocyclyl is optionally substituted with halogen.
 28. The compoundaccording to claim 27, wherein in the W, the NH(R₆) is:


29. A composition comprising a compound according to any one of claims1-4 or a pharmaceutically acceptable salt, derivative or prodrug thereofin an amount effective to inhibit a serine protease; and a acceptablecarrier, adjuvant or vehicle.
 30. The composition according to claim 29,wherein said composition is formulated for administration to a patient.31. The composition according to claim 30, wherein said compositioncomprises an additional agent selected from an immunomodulatory agent;an antiviral agent; a second inhibitor of HCV protease; an inhibitor ofanother target in the HCV life cycle; or combinations thereof.
 32. Thecomposition according to claim 31, wherein said immunomodulatory agentis α-, β-, or γ-interferon; the antiviral agent is ribavirin oramantadine; or the inhibitor of another target in the HCV life cycle isan inhibitor of HCV helicase, polymerase, or metalloprotease.
 33. Amethod of inhibiting the activity of a serine protease comprising thestep of contacting said serine protease with a compound according to anyone of claims 1-4.
 34. The method according to claim 33, wherein saidprotease is an HCV NS3 protease.
 35. A method of treating an HCVinfection in a patient comprising the step of administering to saidpatient a composition according to claim
 30. 36. The method according toclaim 34, comprising the additional step of administering to saidpatient an additional agent selected from an immunomodulatory agent; anantiviral agent; a second inhibitor of HCV protease; an inhibitor ofanother target in the HCV life cycle; or combinations thereof; whereinsaid additional agent is administered to said patient as part of saidcomposition according to claim 30 or as a separate dosage form.
 37. Themethod according to claim 36, wherein said immunomodulatory agent is α-,β-, or γ-interferon; said antiviral agent is ribavarin or amantadine; orsaid inhibitor of another target in the HCV life cycle is an inhibitorof HCV helicase, polymerase, or metalloprotease.
 38. A method ofeliminating or reducing HCV contamination of a biological sample ormedical or laboratory equipment, comprising the step of contacting saidbiological sample or medical or laboratory equipment with a compositionaccording to claim
 29. 39. The method according to claim 38, whereinsaid sample or equipment is selected from blood, other body fluids,biological tissue, a surgical instrument, a surgical garment, alaboratory instrument, a laboratory garment, a blood or other body fluidcollection apparatus; a blood or other bodily fluid storage material.